New Therapeutic Implications of Endothelial Nitric Oxide Synthase (eNOS) Function/Dysfunction in Cardiovascular Disease

Andreas Daiber, Ning Xia, Sebastian Steven, Matthias Oelze, Alina Hanf, Swenja Kröller-Schön, Thomas Münzel, Huige Li, Andreas Daiber, Ning Xia, Sebastian Steven, Matthias Oelze, Alina Hanf, Swenja Kröller-Schön, Thomas Münzel, Huige Li

Abstract

The Global Burden of Disease Study identified cardiovascular risk factors as leading causes of global deaths and life years lost. Endothelial dysfunction represents a pathomechanism that is associated with most of these risk factors and stressors, and represents an early (subclinical) marker/predictor of atherosclerosis. Oxidative stress is a trigger of endothelial dysfunction and it is a hall-mark of cardiovascular diseases and of the risk factors/stressors that are responsible for their initiation. Endothelial function is largely based on endothelial nitric oxide synthase (eNOS) function and activity. Likewise, oxidative stress can lead to the loss of eNOS activity or even "uncoupling" of the enzyme by adverse regulation of well-defined "redox switches" in eNOS itself or up-/down-stream signaling molecules. Of note, not only eNOS function and activity in the endothelium are essential for vascular integrity and homeostasis, but also eNOS in perivascular adipose tissue plays an important role for these processes. Accordingly, eNOS protein represents an attractive therapeutic target that, so far, was not pharmacologically exploited. With our present work, we want to provide an overview on recent advances and future therapeutic strategies that could be used to target eNOS activity and function in cardiovascular (and other) diseases, including life style changes and epigenetic modulations. We highlight the redox-regulatory mechanisms in eNOS function and up- and down-stream signaling pathways (e.g., tetrahydrobiopterin metabolism and soluble guanylyl cyclase/cGMP pathway) and their potential pharmacological exploitation.

Keywords: cardiovascular disease; eNOS uncoupling; endothelial dysfunction; environmental stressors; inflammation; life style/behavioral health risk factors; oxidative stress.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Impact of oxidative stress and inflammation markers on cardiovascular events or mortality. (A) Associations of derivatives of reactive oxygen metabolites (d-ROMs) levels and total thiol levels (TTL) with cardiovascular disease-specific mortality Adjustments for other confounders as described for model 1 (age and sex). d-ROMs groups [Carratelli Units]: reference, <340; T1, 341–400; T2, 401–500; T3, >500. *, p < 0.05 versus reference value. Graph was generated from tabular data in Schöttker et al. BMC Med. 2015 [38]. (B) Hazard ratios for all coronary heart disease in correlation with markers of inflammation (cytokines and chemokines: IL-6, IL-18, MMP-9, sCD40L, and TNF-α) in the Danish Research Centre for Prevention and Health cohort (1514 subjects, 833 cases). Adjustment for sex and age, log-transformed baseline levels of cytokines. Redrawn from tabular data in Kaptoge et al. Eur. Heart J. 2014 [46].
Figure 2
Figure 2
Invasive and non-invasive methods for the determination of endothelial function. (A) Acetylcholine (ACh)-dependent vasoreactivity of coronary vessels caused by intra-coronary ACh infusion. Vasodilation and stenotic areas are monitored by angiographic imaging and Doppler ultrasound (blood flow). (B) ACh-dependent vasoreactivity of capacity vessels of the forearm upon intra-arterial ACh infusion. Vasodilation is recorded by Doppler ultrasound (diameter and blood flow). (C) Flow-mediated dilation (FMD) of capacity vessels of the forearm (brachial artery) upon occlusion/ischemia and reperfusion/hyperemia. Vasodilation is recorded by Doppler ultrasound (diameter and blood flow). Maximal vasoreactivity/dilation is determined by sublingual administration of nitroglycerin (NTG). Adapted from [86]. With permission of Taylor & Francis (Abingdon, Oxfordshire, UK). Copyright © 2008, Rights Managed by Taylor & Francis (Abingdon, Oxfordshire, UK). (D) Peripheral arterial tonometry (PAT) measures volume changes and pulse waves by a finger probe that assesses digital volume changes and pulse waves that can be detected after induction of reactive hyperemia. Adopted from Daiber et al., Br. J. Pharmacol. 2017 [13]. With permission of the publisher. Copyright © 2016, John Wiley and Sons (Hoboken, NJ, USA).
Figure 3
Figure 3
Expression of endothelial nitric oxide synthase (eNOS) in perivascular adipose tissue (PVAT) adipocytes. eNOS immunohistochemistry staining and western blot analyses were performed using PVAT-containing aorta samples from C57BL/6J wild-type mice (WT) or global eNOS knockout mice (KO). E and P indicate endothelium and PVAT respectively. Reproduced from Xia et al. Br. J. Pharmacol. 2017 [107], an open access article under the terms of the Creative Commons Attribution-Non-Commercial License CC BY-NC. Copyright © 2017, handled by John Wiley and Sons (Hoboken, NJ, USA).
Figure 4
Figure 4
Role of PVAT in obesity-induced vascular dysfunction. C57BL/6Jmice were fed a high-fat diet (HFD) or normal control diet (NCD) for 20 weeks starting at the age of eight weeks. The vasodilator response to acetylcholine (A–C) was performed in noradrenaline-precontracted aorta with or without PVAT in the absence or presence of the NO synthase inhibitor L-NAME. *** p < 0.001, n = 8. To detect PVAT NO production, NCD and HFD aorta samples were mounted back-to-back on the same slide to guarantee identical staining conditions for the two samples (D). NO production in PVAT-containing aorta was determined by 4,5-diaminofluorescein diacetate (DAF-2 DA) staining. Magnification bar is equal to 200µm. From Xia et al. Arterioscler. Thromb. Vasc. Biol. 2016 [98]. With permission of Wolters Kluwer Health, Inc. (Philadelphia, PA, USA). Copyright © 2015, Wolters Kluwer Health (Philadelphia, PA, USA).
Figure 5
Figure 5
Redox switches in eNOS. X-ray structure of human eNOS based on the protein database entry 3NOS (DOI:10.2210/pdb3nos/pdb) using the PyMOL Molecular Graphics System Version 1.2r1 (DeLano Scientific LLC). The boxes represent the “redox switches” in eNOS such as S-glutathionylation, PKC- and PYK-2 dependent phosphorylation, oxidative BH4 depletion, disruption of the zinc-sulfur-cluster, as well as ADMA synthesis/degradation, all of which contribute to the regulation of its enzymatic activity. GSH, glutathione; GSSG, glutathione disulfide. From Schulz et al., Antioxid. Redox Signal. 2014 [20]. With permission of Mary Ann Liebert Inc. (New Rochelle, NY, USA). Copyright © 2014, Mary Ann Liebert, Inc. (New Rochelle, NY, USA).
Figure 6
Figure 6
Summary of redox regulatory pathways of vascular tone. Endothelial nitric oxide synthase (eNOS) and soluble guanylyl cyclase (sGC) are inactivated by a number of redox switches. Reactive oxygen and nitrogen species (ROS/RNS) also activate the 26S proteasome via 3-nitrotyrosine (3NT) modification leading to degradation of the tetrahydrobiopterin (BH4) synthase GTP-cyclohydrolase (GCH-1) and the BH2 to BH4 recycling enzyme dihydrofolate reductase (DHFR). BH4 is an essential cofactor of eNOS and also prevents oxidative inactivation of the sGC. NO is inactivated by superoxide and eNOS-derived NO prevents proteasomal DHFR degradation upon tyrosine nitration of the 26S proteasome. From Münzel and Daiber, Arterioscler. Thromb. Vasc. Biol. 2015 [135]. With permission of Wolters Kluwer Health, Inc. (Philadelphia, PA, USA). Copyright © 2015, Wolters Kluwer Health (Philadelphia, PA, USA).
Figure 7
Figure 7
Improvement of endothelial function ex vivo by sepiapterin and in vivo by BH4. The effects of sepiapterin (100 µmol/L), a BH4 precursor, and polyethylene glycolated-superoxide dismutase (100 U/mL) pretreatment of aortic rings from angiotensin-II (AT-II)–infused rats (A) or spontaneously hypertensive rats (SHR, B) for 1 h were determined in separate experiments. Data shown are representative for at least three animals or at least six aortic rings/group. p < 0.05: * vs. WKY/Control; $ vs. AT-II/BH4. The statistics were based on one-way-ANOVA comparison of pD2-values and efficacies but also on comparisons of all concentrations in all groups by two-way-ANOVA analysis (for sake of clarity significance is not shown for all data points). From Schuhmacher et al., Hypertension 2010 [230]. With permission of Wolters Kluwer Health, Inc. (Philadelphia, PA, USA). Copyright © 2010, Wolters Kluwer Health (Philadelphia, PA, USA). (C) Effect of tetrahydrobiopterin (BH4) and tetrahydroneopterin (NH4) on the acetylcholine (ACh) dose-response relationship in chronic smokers. BH4 significantly improved ACh dose-response relationship, whereas NH4 was ineffective. Modified from Heitzer et al., Circ. Res. 2000 [233] and published in Schulz et al. Antioxid. Redox Signal. 2008 [119]. With permission of Mary Ann Liebert, Inc. (New Rochelle, NY, USA). Copyright © 2008, Mary Ann Liebert, Inc. (New Rochelle, NY, USA).
Figure 8
Figure 8
Initiators of endothelial (vascular) dysfunction. Inflammation and oxidative stress are strong triggers of endothelial (vascular) dysfunction. Of note, pathomechanisms of classical and environmental risk factors (see top of the scheme) converge to a certain extent at the level of inflammation and oxidative stress to further trigger the down-stream dysregulation and damage: eNOS uncoupling, sGC oxidation (maybe also imbalanced phosphodiesterase expression/activity), prostacyclin synthase (PGIS) nitration and inactivation, redox-triggered endothelin-1 (ET-1) signaling, activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic activation (catecholamines), and finally, AGE/RAGE signaling. In addition, dysregulated arginase metabolism decreases levels of the eNOS substrate L-arginine. The quality of high density lipoprotein (HDL) changes under oxidative stress conditions and metabolic disease. Epigenetic mechanisms also contribute to the (dys)regulation of eNOS expression and activity. The boxes with red lining are discussed in detail in the present review. Modified from Daiber et al., Br. J. Pharmacol. 2017 [13]. With permission of John Wiley and Sons. (Hoboken, NJ, USA). Copyright © 2016, John Wiley and Sons (Hoboken, NJ, USA).

References

    1. Munzel T., Gori T., Keaney J.F., Jr., Maack C., Daiber A. Pathophysiological role of oxidative stress in systolic and diastolic heart failure and its therapeutic implications. Eur. Heart J. 2015;36:2555–2564. doi: 10.1093/eurheartj/ehv305.
    1. Lim S.S., Vos T., Flaxman A.D., Danaei G., Shibuya K., Adair-Rohani H., Amann M., Anderson H.R., Andrews K.G., Aryee M., et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: A systematic analysis for the global burden of disease study 2010. Lancet. 2012;380:2224–2260. doi: 10.1016/S0140-6736(12)61766-8.
    1. Murray C.J., Ezzati M., Flaxman A.D., Lim S., Lozano R., Michaud C., Naghavi M., Salomon J.A., Shibuya K., Vos T., et al. GBD 2010: Design, definitions, and metrics. Lancet. 2012;380:2063–2066. doi: 10.1016/S0140-6736(12)61899-6.
    1. Cohen A.J., Brauer M., Burnett R., Anderson H.R., Frostad J., Estep K., Balakrishnan K., Brunekreef B., Dandona L., Dandona R., et al. Estimates and 25-year trends of the global burden of disease attributable to ambient air pollution: An analysis of data from the global burden of diseases study 2015. Lancet. 2017;389:1907–1918. doi: 10.1016/S0140-6736(17)30505-6.
    1. Munzel T., Gori T., Al-Kindi S., Deanfield J., Lelieveld J., Daiber A., Rajagopalan S. Effects of gaseous and solid constituents of air pollution on endothelial function. Eur. Heart J. 2018;39:3543–3550. doi: 10.1093/eurheartj/ehy481.
    1. Munzel T., Schmidt F.P., Steven S., Herzog J., Daiber A., Sorensen M. Environmental noise and the cardiovascular system. J. Am. Coll. Cardiol. 2018;71:688–697. doi: 10.1016/j.jacc.2017.12.015.
    1. Yusuf S., Hawken S., Ounpuu S., Dans T., Avezum A., Lanas F., McQueen M., Budaj A., Pais P., Varigos J., et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): Case-control study. Lancet. 2004;364:937–952. doi: 10.1016/S0140-6736(04)17018-9.
    1. Rosengren A., Hawken S., Ounpuu S., Sliwa K., Zubaid M., Almahmeed W.A., Blackett K.N., Sitthi-amorn C., Sato H., Yusuf S., et al. Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): Case-control study. Lancet. 2004;364:953–962. doi: 10.1016/S0140-6736(04)17019-0.
    1. Siegrist J., Sies H. Disturbed redox homeostasis in oxidative distress: A molecular link from chronic psychosocial work stress to coronary heart disease? Circ. Res. 2017;121:103–105. doi: 10.1161/CIRCRESAHA.117.311182.
    1. Schiavone S., Jaquet V., Trabace L., Krause K.H. Severe life stress and oxidative stress in the brain: From animal models to human pathology. Antioxid. Redox Signal. 2013;18:1475–1490. doi: 10.1089/ars.2012.4720.
    1. Vita J.A., Treasure C.B., Nabel E.G., McLenachan J.M., Fish R.D., Yeung A.C., Vekshtein V.I., Selwyn A.P., Ganz P. Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation. 1990;81:491–497. doi: 10.1161/01.CIR.81.2.491.
    1. Panza J.A., Quyyumi A.A., Brush J.E., Jr., Epstein S.E. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N. Engl. J. Med. 1990;323:22–27. doi: 10.1056/NEJM199007053230105.
    1. Daiber A., Steven S., Weber A., Shuvaev V.V., Muzykantov V.R., Laher I., Li H., Lamas S., Munzel T. Targeting vascular (endothelial) dysfunction. Br. J. Pharmacol. 2017;174:1591–1619. doi: 10.1111/bph.13517.
    1. Munzel T., Daiber A. Environmental stressors and their impact on health and disease with focus on oxidative stress. Antioxid. Redox Signal. 2018;28:735–740. doi: 10.1089/ars.2017.7488.
    1. Griendling K.K., FitzGerald G.A. Oxidative stress and cardiovascular injury: Part I: Basic mechanisms and in vivo monitoring of ROS. Circulation. 2003;108:1912–1916. doi: 10.1161/.
    1. Griendling K.K., FitzGerald G.A. Oxidative stress and cardiovascular injury: Part II: Animal and human studies. Circulation. 2003;108:2034–2040. doi: 10.1161/01.CIR.0000093661.90582.c4.
    1. Sies H. Oxidative stress: A concept in redox biology and medicine. Redox Biol. 2015;4:180–183. doi: 10.1016/j.redox.2015.01.002.
    1. Ohara Y., Peterson T.E., Harrison D.G. Hypercholesterolemia increases endothelial superoxide anion production. J. Clin. Investig. 1993;91:2546–2551. doi: 10.1172/JCI116491.
    1. Harrison D.G., Ohara Y. Physiologic consequences of increased vascular oxidant stresses in hypercholesterolemia and atherosclerosis: Implications for impaired vasomotion. Am. J. Cardiol. 1995;75:75B–81B. doi: 10.1016/0002-9149(95)80018-N.
    1. Schulz E., Wenzel P., Munzel T., Daiber A. Mitochondrial redox signaling: Interaction of mitochondrial reactive oxygen species with other sources of oxidative stress. Antioxid. Redox Signal. 2014;20:308–324. doi: 10.1089/ars.2012.4609.
    1. Forstermann U., Munzel T. Endothelial nitric oxide synthase in vascular disease: From marvel to menace. Circulation. 2006;113:1708–1714. doi: 10.1161/CIRCULATIONAHA.105.602532.
    1. Munzel T., Daiber A., Ullrich V., Mulsch A. Vascular consequences of endothelial nitric oxide synthase uncoupling for the activity and expression of the soluble guanylyl cyclase and the cGMP-dependent protein kinase. Arterioscler. Thromb. Vasc. Biol. 2005;25:1551–1557. doi: 10.1161/.
    1. Daiber A., Oelze M., Daub S., Steven S., Schuff A., Kroller-Schon S., Hausding M., Wenzel P., Schulz E., Gori T., et al. Vascular redox signaling, redox switches in endothelial nitric oxide synthase and endothelial dysfunction. In: Laher I., editor. Systems Biology of Free Radicals and Antioxidants. Springer; Berlin/Heidelberg, Germany: 2014. pp. 1177–1211.
    1. Zorov D.B., Juhaszova M., Sollott S.J. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol. Rev. 2014;94:909–950. doi: 10.1152/physrev.00026.2013.
    1. Daiber A. Redox signaling (cross-talk) from and to mitochondria involves mitochondrial pores and reactive oxygen species. Biochim. Biophys. Acta. 2010;1797:897–906. doi: 10.1016/j.bbabio.2010.01.032.
    1. Heitzer T., Schlinzig T., Krohn K., Meinertz T., Munzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation. 2001;104:2673–2678. doi: 10.1161/hc4601.099485.
    1. Schachinger V., Britten M.B., Zeiher A.M. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000;101:1899–1906. doi: 10.1161/01.CIR.101.16.1899.
    1. Nakazono K., Watanabe N., Matsuno K., Sasaki J., Sato T., Inoue M. Does superoxide underlie the pathogenesis of hypertension? Proc. Natl. Acad. Sci. USA. 1991;88:10045–10048. doi: 10.1073/pnas.88.22.10045.
    1. Rajagopalan S., Kurz S., Munzel T., Tarpey M., Freeman B.A., Griendling K.K., Harrison D.G. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J. Clin. Investig. 1996;97:1916–1923. doi: 10.1172/JCI118623.
    1. Mollnau H., Wendt M., Szocs K., Lassegue B., Schulz E., Oelze M., Li H., Bodenschatz M., August M., Kleschyov A.L., et al. Effects of angiotensin ii infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling. Circ. Res. 2002;90:e58–e65. doi: 10.1161/01.RES.0000012569.55432.02.
    1. Landmesser U., Cai H., Dikalov S., McCann L., Hwang J., Jo H., Holland S.M., Harrison D.G. Role of p47(phox) in vascular oxidative stress and hypertension caused by angiotensin II. Hypertension. 2002;40:511–515. doi: 10.1161/01.HYP.0000032100.23772.98.
    1. Kuzkaya N., Weissmann N., Harrison D.G., Dikalov S. Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: Implications for uncoupling endothelial nitric-oxide synthase. J. Biol. Chem. 2003;278:22546–22554. doi: 10.1074/jbc.M302227200.
    1. Landmesser U., Dikalov S., Price S.R., McCann L., Fukai T., Holland S.M., Mitch W.E., Harrison D.G. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J. Clin. Investig. 2003;111:1201–1209. doi: 10.1172/JCI200314172.
    1. Fratta Pasini A., Albiero A., Stranieri C., Cominacini M., Pasini A., Mozzini C., Vallerio P., Cominacini L., Garbin U. Serum oxidative stress-induced repression of Nrf2 and GSH depletion: A mechanism potentially involved in endothelial dysfunction of young smokers. PLoS ONE. 2012;7:e30291. doi: 10.1371/journal.pone.0030291.
    1. Yilmaz M.I., Saglam M., Caglar K., Cakir E., Sonmez A., Ozgurtas T., Aydin A., Eyileten T., Ozcan O., Acikel C., et al. The determinants of endothelial dysfunction in CKD: Oxidative stress and asymmetric dimethylarginine. Am. J. Kidney Dis. 2006;47:42–50. doi: 10.1053/j.ajkd.2005.09.029.
    1. Jurado-Gamez B., Fernandez-Marin M.C., Gomez-Chaparro J.L., Munoz-Cabrera L., Lopez-Barea J., Perez-Jimenez F., Lopez-Miranda J. Relationship of oxidative stress and endothelial dysfunction in sleep apnoea. Eur. Respir. J. 2011;37:873–879. doi: 10.1183/09031936.00027910.
    1. Blankenberg S., Rupprecht H.J., Bickel C., Torzewski M., Hafner G., Tiret L., Smieja M., Cambien F., Meyer J., Lackner K.J. Glutathione peroxidase 1 activity and cardiovascular events in patients with coronary artery disease. N. Engl. J. Med. 2003;349:1605–1613. doi: 10.1056/NEJMoa030535.
    1. Schottker B., Brenner H., Jansen E.H., Gardiner J., Peasey A., Kubinova R., Pajak A., Topor-Madry R., Tamosiunas A., Saum K.U., et al. Evidence for the free radical/oxidative stress theory of ageing from the CHANCES consortium: A meta-analysis of individual participant data. BMC Med. 2015;13:300. doi: 10.1186/s12916-015-0537-7.
    1. Khaw K.T., Bingham S., Welch A., Luben R., Wareham N., Oakes S., Day N. Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: A prospective population study. European prospective investigation into cancer and nutrition. Lancet. 2001;357:657–663. doi: 10.1016/S0140-6736(00)04128-3.
    1. Munzel T., Gori T., Bruno R.M., Taddei S. Is oxidative stress a therapeutic target in cardiovascular disease? Eur. Heart J. 2010;31:2741–2748. doi: 10.1093/eurheartj/ehq396.
    1. Schmidt H.H., Stocker R., Vollbracht C., Paulsen G., Riley D., Daiber A., Cuadrado A. Antioxidants in translational medicine. Antioxid. Redox Signal. 2015;23:1130–1143. doi: 10.1089/ars.2015.6393.
    1. Shuaib A., Lees K.R., Lyden P., Grotta J., Davalos A., Davis S.M., Diener H.C., Ashwood T., Wasiewski W.W., Emeribe U., et al. NXY-059 for the treatment of acute ischemic stroke. N. Engl. J. Med. 2007;357:562–571. doi: 10.1056/NEJMoa070240.
    1. Karbach S., Wenzel P., Waisman A., Munzel T., Daiber A. eNOS uncoupling in cardiovascular diseases—The role of oxidative stress and inflammation. Curr. Pharm. Des. 2014;20:3579–3594. doi: 10.2174/13816128113196660748.
    1. Harrison D.G., Guzik T.J., Lob H.E., Madhur M.S., Marvar P.J., Thabet S.R., Vinh A., Weyand C.M. Inflammation, immunity, and hypertension. Hypertension. 2011;57:132–140. doi: 10.1161/HYPERTENSIONAHA.110.163576.
    1. Wenzel P., Kossmann S., Munzel T., Daiber A. Redox regulation of cardiovascular inflammation—Immunomodulatory function of mitochondrial and Nox-derived reactive oxygen and nitrogen species. Free Radic. Biol. Med. 2017;109:48–60. doi: 10.1016/j.freeradbiomed.2017.01.027.
    1. Kaptoge S., Seshasai S.R., Gao P., Freitag D.F., Butterworth A.S., Borglykke A., Di Angelantonio E., Gudnason V., Rumley A., Lowe G.D., et al. Inflammatory cytokines and risk of coronary heart disease: New prospective study and updated meta-analysis. Eur. Heart J. 2014;35:578–589. doi: 10.1093/eurheartj/eht367.
    1. Ridker P.M., Everett B.M., Thuren T., MacFadyen J.G., Chang W.H., Ballantyne C., Fonseca F., Nicolau J., Koenig W., Anker S.D., et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 2017;377:1119–1131. doi: 10.1056/NEJMoa1707914.
    1. Cave A.C., Brewer A.C., Narayanapanicker A., Ray R., Grieve D.J., Walker S., Shah A.M. NADPH oxidases in cardiovascular health and disease. Antioxid. Redox Signal. 2006;8:691–728. doi: 10.1089/ars.2006.8.691.
    1. Guzik T.J., Hoch N.E., Brown K.A., McCann L.A., Rahman A., Dikalov S., Goronzy J., Weyand C., Harrison D.G. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J. Exp. Med. 2007;204:2449–2460. doi: 10.1084/jem.20070657.
    1. Wenzel P., Knorr M., Kossmann S., Stratmann J., Hausding M., Schuhmacher S., Karbach S.H., Schwenk M., Yogev N., Schulz E., et al. Lysozyme M-positive monocytes mediate angiotensin II-induced arterial hypertension and vascular dysfunction. Circulation. 2011;124:1370–1381. doi: 10.1161/CIRCULATIONAHA.111.034470.
    1. Bulua A.C., Simon A., Maddipati R., Pelletier M., Park H., Kim K.Y., Sack M.N., Kastner D.L., Siegel R.M. Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS) J. Exp. Med. 2011;208:519–533. doi: 10.1084/jem.20102049.
    1. West A.P., Brodsky I.E., Rahner C., Woo D.K., Erdjument-Bromage H., Tempst P., Walsh M.C., Choi Y., Shadel G.S., Ghosh S. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature. 2011;472:476–480. doi: 10.1038/nature09973.
    1. Zhou R., Yazdi A.S., Menu P., Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469:221–225. doi: 10.1038/nature09663.
    1. Mittal M., Siddiqui M.R., Tran K., Reddy S.P., Malik A.B. Reactive oxygen species in inflammation and tissue injury. Antioxid. Redox Signal. 2014;20:1126–1167. doi: 10.1089/ars.2012.5149.
    1. El Assar M., Angulo J., Rodriguez-Manas L. Oxidative stress and vascular inflammation in aging. Free Radic. Biol. Med. 2013;65:380–401. doi: 10.1016/j.freeradbiomed.2013.07.003.
    1. Mikhed Y., Daiber A., Steven S. Mitochondrial oxidative stress, mitochondrial DNA damage and their role in age-related vascular dysfunction. Int. J. Mol. Sci. 2015;16:15918–15953. doi: 10.3390/ijms160715918.
    1. Yang J., Zheng X., Mahdi A., Zhou Z., Tratsiakovich Y., Jiao T., Kiss A., Kovamees O., Alvarsson M., Catrina S.B., et al. Red blood cells in type 2 diabetes impair cardiac post-ischemic recovery through an arginase-dependent modulation of nitric oxide synthase and reactive oxygen species. JACC Basic Transl. Sci. 2018;3:450–463. doi: 10.1016/j.jacbts.2018.03.006.
    1. Zhou Z., Mahdi A., Tratsiakovich Y., Zahoran S., Kovamees O., Nordin F., Uribe Gonzalez A.E., Alvarsson M., Ostenson C.G., Andersson D.C., et al. Erythrocytes from patients with type 2 diabetes induce endothelial dysfunction via arginase I. J. Am. Coll. Cardiol. 2018;72:769–780. doi: 10.1016/j.jacc.2018.05.052.
    1. Soltesz P., Kerekes G., Der H., Szucs G., Szanto S., Kiss E., Bodolay E., Zeher M., Timar O., Szodoray P., et al. Comparative assessment of vascular function in autoimmune rheumatic diseases: Considerations of prevention and treatment. Autoimmun. Rev. 2011;10:416–425. doi: 10.1016/j.autrev.2011.01.004.
    1. Murdaca G., Colombo B.M., Cagnati P., Gulli R., Spano F., Puppo F. Endothelial dysfunction in rheumatic autoimmune diseases. Atherosclerosis. 2012;224:309–317. doi: 10.1016/j.atherosclerosis.2012.05.013.
    1. Vena G.A., Vestita M., Cassano N. Psoriasis and cardiovascular disease. Dermatol. Ther. 2010;23:144–151. doi: 10.1111/j.1529-8019.2010.01308.x.
    1. Hak A.E., Karlson E.W., Feskanich D., Stampfer M.J., Costenbader K.H. Systemic lupus erythematosus and the risk of cardiovascular disease: Results from the nurses’ health study. Arthritis Care Res. 2009;61:1396–1402. doi: 10.1002/art.24537.
    1. Mehta N.N., Azfar R.S., Shin D.B., Neimann A.L., Troxel A.B., Gelfand J.M. Patients with severe psoriasis are at increased risk of cardiovascular mortality: Cohort study using the general practice research database. Eur. Heart J. 2010;31:1000–1006. doi: 10.1093/eurheartj/ehp567.
    1. Peters M.J., Symmons D.P., McCarey D., Dijkmans B.A., Nicola P., Kvien T.K., McInnes I.B., Haentzschel H., Gonzalez-Gay M.A., Provan S., et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann. Rheum. Dis. 2010;69:325–331. doi: 10.1136/ard.2009.113696.
    1. Herrera J., Ferrebuz A., MacGregor E.G., Rodriguez-Iturbe B. Mycophenolate mofetil treatment improves hypertension in patients with psoriasis and rheumatoid arthritis. J. Am. Soc. Nephrol. 2006;17:S218–S225. doi: 10.1681/ASN.2006080918.
    1. Sodergren A., Karp K., Boman K., Eriksson C., Lundstrom E., Smedby T., Soderlund L., Rantapaa-Dahlqvist S., Wallberg-Jonsson S. Atherosclerosis in early rheumatoid arthritis: Very early endothelial activation and rapid progression of intima media thickness. Arthritis Res. Ther. 2010;12:R158. doi: 10.1186/ar3116.
    1. Balci D.D., Balci A., Karazincir S., Ucar E., Iyigun U., Yalcin F., Seyfeli E., Inandi T., Egilmez E. Increased carotid artery intima-media thickness and impaired endothelial function in psoriasis. J. Eur. Acad. Dermatol. Venereol. 2009;23:1–6. doi: 10.1111/j.1468-3083.2008.02936.x.
    1. Di Cesare A., Di Meglio P., Nestle F.O. The IL-23/Th17 axis in the immunopathogenesis of psoriasis. J. Investig. Dermatol. 2009;129:1339–1350. doi: 10.1038/jid.2009.59.
    1. Leonardi C., Matheson R., Zachariae C., Cameron G., Li L., Edson-Heredia E., Braun D., Banerjee S. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N. Engl. J. Med. 2012;366:1190–1199. doi: 10.1056/NEJMoa1109997.
    1. Papp K.A., Leonardi C., Menter A., Ortonne J.P., Krueger J.G., Kricorian G., Aras G., Li J., Russell C.B., Thompson E.H., et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N. Engl. J. Med. 2012;366:1181–1189. doi: 10.1056/NEJMoa1109017.
    1. Crispin J.C., Tsokos G.C. IL-17 in systemic lupus erythematosus. J. Biomed. Biotechnol. 2010;2010:943254. doi: 10.1155/2010/943254.
    1. Choy E. Understanding the dynamics: Pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology. 2012;51(Suppl. 5):v3–v11. doi: 10.1093/rheumatology/kes113.
    1. Pasceri V., Yeh E.T. A tale of two diseases: Atherosclerosis and rheumatoid arthritis. Circulation. 1999;100:2124–2126. doi: 10.1161/01.CIR.100.21.2124.
    1. Perticone F., Ceravolo R., Pujia A., Ventura G., Iacopino S., Scozzafava A., Ferraro A., Chello M., Mastroroberto P., Verdecchia P., et al. Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation. 2001;104:191–196. doi: 10.1161/01.CIR.104.2.191.
    1. Calver A., Collier J., Vallance P. Inhibition and stimulation of nitric oxide synthesis in the human forearm arterial bed of patients with insulin-dependent diabetes. J. Clin. Investig. 1992;90:2548–2554. doi: 10.1172/JCI116149.
    1. Celermajer D.S., Sorensen K.E., Georgakopoulos D., Bull C., Thomas O., Robinson J., Deanfield J.E. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation. 1993;88:2149–2155. doi: 10.1161/01.CIR.88.5.2149.
    1. Gonzalez M.A., Selwyn A.P. Endothelial function, inflammation, and prognosis in cardiovascular disease. Am. J. Med. 2003;115(Suppl. 1):99–106. doi: 10.1016/j.amjmed.2003.09.016.
    1. Pauriah M., Khan F., Lim T.K., Elder D.H., Godfrey V., Kennedy G., Belch J.J., Booth N.A., Struthers A.D., Lang C.C. B-type natriuretic peptide is an independent predictor of endothelial function in man. Clin. Sci. 2012;123:307–312. doi: 10.1042/CS20110168.
    1. Okui H., Hamasaki S., Ishida S., Kataoka T., Orihara K., Fukudome T., Ogawa M., Oketani N., Saihara K., Shinsato T., et al. Adiponectin is a better predictor of endothelial function of the coronary artery than HOMA-R, body mass index, immunoreactive insulin, or triglycerides. Int. J. Cardiol. 2008;126:53–61. doi: 10.1016/j.ijcard.2007.03.116.
    1. Schmidt F.P., Basner M., Kroger G., Weck S., Schnorbus B., Muttray A., Sariyar M., Binder H., Gori T., Warnholtz A., et al. Effect of nighttime aircraft noise exposure on endothelial function and stress hormone release in healthy adults. Eur. Heart J. 2013;34:3508–3514. doi: 10.1093/eurheartj/eht269.
    1. Schmidt F., Kolle K., Kreuder K., Schnorbus B., Wild P., Hechtner M., Binder H., Gori T., Munzel T. Nighttime aircraft noise impairs endothelial function and increases blood pressure in patients with or at high risk for coronary artery disease. Clin. Res. Cardiol. 2015;104:23–30. doi: 10.1007/s00392-014-0751-x.
    1. Mills N.L., Tornqvist H., Robinson S.D., Gonzalez M., Darnley K., MacNee W., Boon N.A., Donaldson K., Blomberg A., Sandstrom T., et al. Diesel exhaust inhalation causes vascular dysfunction and impaired endogenous fibrinolysis. Circulation. 2005;112:3930–3936. doi: 10.1161/CIRCULATIONAHA.105.588962.
    1. Brook R.D., Urch B., Dvonch J.T., Bard R.L., Speck M., Keeler G., Morishita M., Marsik F.J., Kamal A.S., Kaciroti N., et al. Insights into the mechanisms and mediators of the effects of air pollution exposure on blood pressure and vascular function in healthy humans. Hypertension. 2009;54:659–667. doi: 10.1161/HYPERTENSIONAHA.109.130237.
    1. Ghiadoni L., Donald A.E., Cropley M., Mullen M.J., Oakley G., Taylor M., O’Connor G., Betteridge J., Klein N., Steptoe A., et al. Mental stress induces transient endothelial dysfunction in humans. Circulation. 2000;102:2473–2478. doi: 10.1161/01.CIR.102.20.2473.
    1. Broadley A.J., Korszun A., Abdelaal E., Moskvina V., Jones C.J., Nash G.B., Ray C., Deanfield J., Frenneaux M.P. Inhibition of cortisol production with metyrapone prevents mental stress-induced endothelial dysfunction and baroreflex impairment. J. Am. Coll. Cardiol. 2005;46:344–350. doi: 10.1016/j.jacc.2005.03.068.
    1. Munzel T., Sinning C., Post F., Warnholtz A., Schulz E. Pathophysiology, diagnosis and prognostic implications of endothelial dysfunction. Ann. Med. 2008;40:180–196. doi: 10.1080/07853890701854702.
    1. Heitzer T., Ylä-Herttuala S., Luoma J., Kurz S., Munzel T., Just H., Olschewski M., Drexler H. Cigarette smoking potentiates endothelial dysfunction of forearm resistance vessels in patients with hypercholesterolemia: Role of oxidized LDL. Circulation. 1996;93:1346–1353. doi: 10.1161/01.CIR.93.7.1346.
    1. Schnabel R.B., Wild P.S., Schulz A., Zeller T., Sinning C.R., Wilde S., Kunde J., Lubos E., Lackner K.J., Warnholtz A., et al. Multiple endothelial biomarkers and noninvasive vascular function in the general population: The Gutenberg Health Study. Hypertension. 2012;60:288–295. doi: 10.1161/HYPERTENSIONAHA.112.191874.
    1. Garcia M.M., Lima P.R., Correia L.C. Prognostic value of endothelial function in patients with atherosclerosis: Systematic review. Arq. Bras. Cardiol. 2012;99:857–865. doi: 10.1590/S0066-782X2012005000078.
    1. Suessenbacher A., Dorler J., Wunder J., Hohenwarter F., Alber H.F., Pachinger O., Frick M. Comparison of brachial artery wall thickness versus endothelial function to predict late cardiovascular events in patients undergoing elective coronary angiography. Am. J. Cardiol. 2013;111:671–675. doi: 10.1016/j.amjcard.2012.11.020.
    1. Roos W.P., Kaina B. DNA damage-induced cell death: From specific DNA lesions to the DNA damage response and apoptosis. Cancer Lett. 2013;332:237–248. doi: 10.1016/j.canlet.2012.01.007.
    1. Schnabel R.B., Schulz A., Wild P.S., Sinning C.R., Wilde S., Eleftheriadis M., Herkenhoff S., Zeller T., Lubos E., Lackner K.J., et al. Noninvasive vascular function measurement in the community: Cross-sectional relations and comparison of methods. Circ. Cardiovasc. Imaging. 2011;4:371–380. doi: 10.1161/CIRCIMAGING.110.961557.
    1. Mitchell G.F. Arterial stiffness: Insights from Framingham and Iceland. Curr. Opin. Nephrol. Hypertens. 2015;24:1–7. doi: 10.1097/MNH.0000000000000092.
    1. Ashfaq S., Abramson J.L., Jones D.P., Rhodes S.D., Weintraub W.S., Hooper W.C., Vaccarino V., Harrison D.G., Quyyumi A.A. The relationship between plasma levels of oxidized and reduced thiols and early atherosclerosis in healthy adults. J. Am. Coll. Cardiol. 2006;47:1005–1011. doi: 10.1016/j.jacc.2005.09.063.
    1. Soltis E.E., Cassis L.A. Influence of perivascular adipose tissue on rat aortic smooth muscle responsiveness. Clin. Exp. Hypertens. Part A Theory Pract. 1991;13:277–296. doi: 10.3109/10641969109042063.
    1. Xia N., Li H. The role of perivascular adipose tissue in obesity-induced vascular dysfunction. Br. J. Pharmacol. 2017;174:3425–3442. doi: 10.1111/bph.13650.
    1. Dashwood M.R., Dooley A., Shi-Wen X., Abraham D.J., Souza D.S. Does periadventitial fat-derived nitric oxide play a role in improved saphenous vein graft patency in patients undergoing coronary artery bypass surgery? J. Vasc. Res. 2007;44:175–181. doi: 10.1159/000099833.
    1. Xia N., Horke S., Habermeier A., Closs E.I., Reifenberg G., Gericke A., Mikhed Y., Munzel T., Daiber A., Forstermann U., et al. Uncoupling of endothelial nitric oxide synthase in perivascular adipose tissue of diet-induced obese mice. Arterioscler. Thromb. Vasc. Biol. 2016;36:78–85. doi: 10.1161/ATVBAHA.115.306263.
    1. Gil-Ortega M., Stucchi P., Guzman-Ruiz R., Cano V., Arribas S., Gonzalez M.C., Ruiz-Gayo M., Fernandez-Alfonso M.S., Somoza B. Adaptative nitric oxide overproduction in perivascular adipose tissue during early diet-induced obesity. Endocrinology. 2010;151:3299–3306. doi: 10.1210/en.2009-1464.
    1. Victorio J.A., Fontes M.T., Rossoni L.V., Davel A.P. Different anti-contractile function and nitric oxide production of thoracic and abdominal perivascular adipose tissues. Front. Physiol. 2016;7:295. doi: 10.3389/fphys.2016.00295.
    1. Virdis A., Duranti E., Rossi C., Dell’Agnello U., Santini E., Anselmino M., Chiarugi M., Taddei S., Solini A. Tumour necrosis factor-alpha participates on the endothelin-1/nitric oxide imbalance in small arteries from obese patients: Role of perivascular adipose tissue. Eur. Heart J. 2015;36:784–794. doi: 10.1093/eurheartj/ehu072.
    1. Aghamohammadzadeh R., Unwin R.D., Greenstein A.S., Heagerty A.M. Effects of obesity on perivascular adipose tissue vasorelaxant function: Nitric oxide, inflammation and elevated systemic blood pressure. J. Vasc. Res. 2015;52:299–305. doi: 10.1159/000443885.
    1. Bussey C.E., Withers S.B., Aldous R.G., Edwards G., Heagerty A.M. Obesity-related perivascular adipose tissue damage is reversed by sustained weight loss in the rat. Arterioscler. Thromb. Vasc. Biol. 2016;36:1377–1385. doi: 10.1161/ATVBAHA.116.307210.
    1. Li H., Forstermann U. Nitric oxide in the pathogenesis of vascular disease. J. Pathol. 2000;190:244–254. doi: 10.1002/(SICI)1096-9896(200002)190:3<244::AID-PATH575>;2-8.
    1. Withers S.B., Simpson L., Fattah S., Werner M.E., Heagerty A.M. cGMP-dependent protein kinase (PKG) mediates the anticontractile capacity of perivascular adipose tissue. Cardiovasc. Res. 2014;101:130–137. doi: 10.1093/cvr/cvt229.
    1. Weston A.H., Egner I., Dong Y., Porter E.L., Heagerty A.M., Edwards G. Stimulated release of a hyperpolarizing factor (ADHF) from mesenteric artery perivascular adipose tissue: Involvement of myocyte BKCa channels and adiponectin. Br. J. Pharmacol. 2013;169:1500–1509. doi: 10.1111/bph.12157.
    1. Xia N., Weisenburger S., Koch E., Burkart M., Reifenberg G., Forstermann U., Li H. Restoration of perivascular adipose tissue function in diet-induced obese mice without changing bodyweight. Br. J. Pharmacol. 2017;174:3443–3453. doi: 10.1111/bph.13703.
    1. Xia N., Forstermann U., Li H. Effects of resveratrol on eNOS in the endothelium and the perivascular adipose tissue. Ann. N. Y. Acad. Sci. 2017;1403:132–141. doi: 10.1111/nyas.13397.
    1. Sun Y., Li J., Xiao N., Wang M., Kou J., Qi L., Huang F., Liu B., Liu K. Pharmacological activation of AMPK ameliorates perivascular adipose/endothelial dysfunction in a manner interdependent on AMPK and SIRT1. Pharmacol. Res. 2014;89:19–28. doi: 10.1016/j.phrs.2014.07.006.
    1. Chen Y., Xu X., Zhang Y., Liu K., Huang F., Liu B., Kou J. Diosgenin regulates adipokine expression in perivascular adipose tissue and ameliorates endothelial dysfunction via regulation of AMPK. J. Steroid Biochem. Mol. Biol. 2016;155:155–165. doi: 10.1016/j.jsbmb.2015.07.005.
    1. Daiber A., Di Lisa F., Oelze M., Kroller-Schon S., Steven S., Schulz E., Munzel T. Crosstalk of mitochondria with NADPH oxidase via reactive oxygen and nitrogen species signalling and its role for vascular function. Br. J. Pharmacol. 2017;174:1670–1689. doi: 10.1111/bph.13403.
    1. Gryglewski R.J., Palmer R.M., Moncada S. Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature. 1986;320:454–456. doi: 10.1038/320454a0.
    1. Munzel T., Daiber A., Gori T. Nitrate therapy: New aspects concerning molecular action and tolerance. Circulation. 2011;123:2132–2144. doi: 10.1161/CIRCULATIONAHA.110.981407.
    1. Vasquez-Vivar J., Kalyanaraman B., Martasek P., Hogg N., Masters B.S., Karoui H., Tordo P., Pritchard K.A., Jr. Superoxide generation by endothelial nitric oxide synthase: The influence of cofactors. Proc. Natl. Acad. Sci. USA. 1998;95:9220–9225. doi: 10.1073/pnas.95.16.9220.
    1. Guzik T.J., Mussa S., Gastaldi D., Sadowski J., Ratnatunga C., Pillai R., Channon K.M. Mechanisms of increased vascular superoxide production in human diabetes mellitus: Role of NAD(P)H oxidase and endothelial nitric oxide synthase. Circulation. 2002;105:1656–1662. doi: 10.1161/01.CIR.0000012748.58444.08.
    1. Alp N.J., Mussa S., Khoo J., Cai S., Guzik T., Jefferson A., Goh N., Rockett K.A., Channon K.M. Tetrahydrobiopterin-dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I overexpression. J. Clin. Investig. 2003;112:725–735. doi: 10.1172/JCI17786.
    1. Bendall J.K., Alp N.J., Warrick N., Cai S., Adlam D., Rockett K., Yokoyama M., Kawashima S., Channon K.M. Stoichiometric relationships between endothelial tetrahydrobiopterin, endothelial no synthase (eNOS) activity, and eNOS coupling in vivo: Insights from transgenic mice with endothelial-targeted GTP cyclohydrolase 1 and eNOS overexpression. Circ. Res. 2005;97:864–871. doi: 10.1161/01.RES.0000187447.03525.72.
    1. Laursen J.B., Somers M., Kurz S., McCann L., Warnholtz A., Freeman B.A., Tarpey M., Fukai T., Harrison D.G. Endothelial regulation of vasomotion in apoE-deficient mice: Implications for interactions between peroxynitrite and tetrahydrobiopterin. Circulation. 2001;103:1282–1288. doi: 10.1161/01.CIR.103.9.1282.
    1. Schulz E., Jansen T., Wenzel P., Daiber A., Munzel T. Nitric oxide, tetrahydrobiopterin, oxidative stress, and endothelial dysfunction in hypertension. Antioxid. Redox Signal. 2008;10:1115–1126. doi: 10.1089/ars.2007.1989.
    1. Harrison D.G., Chen W., Dikalov S., Li L. Regulation of endothelial cell tetrahydrobiopterin pathophysiological and therapeutic implications. Adv. Pharmacol. 2010;60:107–132.
    1. Bendall J.K., Douglas G., McNeill E., Channon K.M., Crabtree M.J. Tetrahydrobiopterin in cardiovascular health and disease. Antioxid. Redox Signal. 2014;20:3040–3077. doi: 10.1089/ars.2013.5566.
    1. Vasquez-Vivar J. Tetrahydrobiopterin, superoxide, and vascular dysfunction. Free Radic. Biol. Med. 2009;47:1108–1119. doi: 10.1016/j.freeradbiomed.2009.07.024.
    1. Alp N.J., Channon K.M. Regulation of endothelial nitric oxide synthase by tetrahydrobiopterin in vascular disease. Arterioscler. Thromb. Vasc. Biol. 2004;24:413–420. doi: 10.1161/01.ATV.0000110785.96039.f6.
    1. Xu J., Wang S., Wu Y., Song P., Zou M.H. Tyrosine nitration of PA700 activates the 26S proteasome to induce endothelial dysfunction in mice with angiotensin II-induced hypertension. Hypertension. 2009;54:625–632. doi: 10.1161/HYPERTENSIONAHA.109.133736.
    1. Xu J., Wu Y., Song P., Zhang M., Wang S., Zou M.H. Proteasome-dependent degradation of guanosine 5′-triphosphate cyclohydrolase I causes tetrahydrobiopterin deficiency in diabetes mellitus. Circulation. 2007;116:944–953. doi: 10.1161/CIRCULATIONAHA.106.684795.
    1. Whitsett J., Picklo M.J., Sr., Vasquez-Vivar J. 4-hydroxy-2-nonenal increases superoxide anion radical in endothelial cells via stimulated GTP cyclohydrolase proteasomal degradation. Arterioscler. Thromb. Vasc. Biol. 2007;27:2340–2347. doi: 10.1161/ATVBAHA.107.153742.
    1. Munzel T., Daiber A. Does endothelial tetrahydrobiopterin control the endothelial no synthase coupling state in arterial resistance arteries? Br. J. Pharmacol. 2017;174:2422–2424. doi: 10.1111/bph.13827.
    1. Chuaiphichai S., Crabtree M.J., McNeill E., Hale A.B., Trelfa L., Channon K.M., Douglas G. A key role for tetrahydrobiopterin-dependent endothelial NOS regulation in resistance arteries: Studies in endothelial cell tetrahydrobiopterin-deficient mice. Br. J. Pharmacol. 2017;174:657–671. doi: 10.1111/bph.13728.
    1. Douglas G., Hale A.B., Patel J., Chuaiphichai S., Al Haj Zen A., Rashbrook V.S., Trelfa L., Crabtree M.J., McNeill E., Channon K.M. Roles for endothelial cell and macrophage Gch1 and tetrahydrobiopterin in atherosclerosis progression. Cardiovasc. Res. 2018;114:1385–1399. doi: 10.1093/cvr/cvy078.
    1. Munzel T., Daiber A. Role of endothelial and macrophage tetrahydrobiopterin in development and progression of atherosclerosis: BH4 puzzle solved? Cardiovasc. Res. 2018;114:1310–1312. doi: 10.1093/cvr/cvy118.
    1. Kossmann S., Hu H., Steven S., Schonfelder T., Fraccarollo D., Mikhed Y., Brahler M., Knorr M., Brandt M., Karbach S.H., et al. Inflammatory monocytes determine endothelial nitric-oxide synthase uncoupling and nitro-oxidative stress induced by angiotensin II. J. Biol. Chem. 2014;289:27540–27550. doi: 10.1074/jbc.M114.604231.
    1. Chalupsky K., Cai H. Endothelial dihydrofolate reductase: Critical for nitric oxide bioavailability and role in angiotensin II uncoupling of endothelial nitric oxide synthase. Proc. Natl. Acad. Sci. USA. 2005;102:9056–9061. doi: 10.1073/pnas.0409594102.
    1. Ionova I.A., Vasquez-Vivar J., Whitsett J., Herrnreiter A., Medhora M., Cooley B.C., Pieper G.M. Deficient BH4 production via de novo and salvage pathways regulates no responses to cytokines in adult cardiac myocytes. Am. J. Physiol. Heart Circ. Physiol. 2008;295:H2178–H2187. doi: 10.1152/ajpheart.00748.2008.
    1. Cai Z., Lu Q., Ding Y., Wang Q., Xiao L., Song P., Zou M.H. Endothelial nitric oxide synthase-derived nitric oxide prevents dihydrofolate reductase degradation via promoting S-nitrosylation. Arterioscler. Thromb. Vasc. Biol. 2015;35:2366–2373. doi: 10.1161/ATVBAHA.115.305796.
    1. Munzel T., Daiber A. Redox regulation of dihydrofolate reductase: Friend or troublemaker? Arterioscler. Thromb. Vasc. Biol. 2015;35:2261–2262. doi: 10.1161/ATVBAHA.115.306556.
    1. Zou M.H., Shi C., Cohen R.A. Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. J. Clin. Investig. 2002;109:817–826. doi: 10.1172/JCI0214442.
    1. Hein T.W., Singh U., Vasquez-Vivar J., Devaraj S., Kuo L., Jialal I. Human C-reactive protein induces endothelial dysfunction and uncoupling of eNOS in vivo. Atherosclerosis. 2009;206:61–68. doi: 10.1016/j.atherosclerosis.2009.02.002.
    1. Kim J.H., Bugaj L.J., Oh Y.J., Bivalacqua T.J., Ryoo S., Soucy K.G., Santhanam L., Webb A., Camara A., Sikka G., et al. Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiffness in old rats. J. Appl. Physiol. 2009;107:1249–1257. doi: 10.1152/japplphysiol.91393.2008.
    1. Lemarie C.A., Shbat L., Marchesi C., Angulo O.J., Deschenes M.E., Blostein M.D., Paradis P., Schiffrin E.L. Mthfr deficiency induces endothelial progenitor cell senescence via uncoupling of eNOS and downregulation of SIRT1. Am. J. Physiol. Heart Circ. Physiol. 2011;300:H745–H753. doi: 10.1152/ajpheart.00321.2010.
    1. Tokutomi Y., Kataoka K., Yamamoto E., Nakamura T., Fukuda M., Nako H., Toyama K., Dong Y.F., Ahmed K.A., Sawa T., et al. Vascular responses to 8-nitro-cyclic GMP in non-diabetic and diabetic mice. Br. J. Pharmacol. 2011;162:1884–1893. doi: 10.1111/j.1476-5381.2011.01201.x.
    1. Lobysheva I., Rath G., Sekkali B., Bouzin C., Feron O., Gallez B., Dessy C., Balligand J.L. Moderate caveolin-1 downregulation prevents NADPH oxidase-dependent endothelial nitric oxide synthase uncoupling by angiotensin II in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 2011;31:2098–2105. doi: 10.1161/ATVBAHA.111.230623.
    1. Serizawa K., Yogo K., Aizawa K., Tashiro Y., Ishizuka N. Nicorandil prevents endothelial dysfunction due to antioxidative effects via normalisation of NADPH oxidase and nitric oxide synthase in streptozotocin diabetic rats. Cardiovasc. Diabetol. 2011;10:105. doi: 10.1186/1475-2840-10-105.
    1. Faria A.M., Papadimitriou A., Silva K.C., Lopes de Faria J.M., Lopes de Faria J.B. Uncoupling endothelial nitric oxide synthase is ameliorated by green tea in experimental diabetes by re-establishing tetrahydrobiopterin levels. Diabetes. 2012;61:1838–1847. doi: 10.2337/db11-1241.
    1. Fike C.D., Dikalova A., Kaplowitz M.R., Cunningham G., Summar M., Aschner J.L. Rescue treatment with L-citrulline inhibits hypoxia-induced pulmonary hypertension in newborn pigs. Am. J. Respir. Cell Mol. Biol. 2015;53:255–264. doi: 10.1165/rcmb.2014-0351OC.
    1. Davel A.P., Brum P.C., Rossoni L.V. Isoproterenol induces vascular oxidative stress and endothelial dysfunction via a Giα-coupled β2-adrenoceptor signaling pathway. PLoS ONE. 2014;9:e91877. doi: 10.1371/journal.pone.0091877.
    1. Solini A., Rossi C., Duranti E., Taddei S., Natali A., Virdis A. Saxagliptin prevents vascular remodeling and oxidative stress in db/db mice. Role of endothelial nitric oxide synthase uncoupling and cyclooxygenase. Vasc. Pharmacol. 2016;76:62–71. doi: 10.1016/j.vph.2015.10.002.
    1. Musicki B., Burnett A.L. Constitutive NOS uncoupling and NADPH oxidase upregulation in the penis of type 2 diabetic men with erectile dysfunction. Andrology. 2017;5:294–298. doi: 10.1111/andr.12313.
    1. Octavia Y., Kararigas G., de Boer M., Chrifi I., Kietadisorn R., Swinnen M., Duimel H., Verheyen F.K., Brandt M.M., Fliegner D., et al. Folic acid reduces doxorubicin-induced cardiomyopathy by modulating endothelial nitric oxide synthase. J. Cell. Mol. Med. 2017;21:3277–3287. doi: 10.1111/jcmm.13231.
    1. Liu M., Zhang X., Wang B., Wu Q., Li B., Li A., Zhang H., Xiu R. Functional status of microvascular vasomotion is impaired in spontaneously hypertensive rat. Sci. Rep. 2017;7:17080. doi: 10.1038/s41598-017-17013-w.
    1. Couto G.K., Paula S.M., Gomes-Santos I.L., Negrao C.E., Rossoni L.V. Exercise training induces eNOS coupling and restores relaxation in coronary arteries of heart failure rats. Am. J. Physiol. Heart Circ. Physiol. 2018;314:H878–H887. doi: 10.1152/ajpheart.00624.2017.
    1. Santana M.N.S., Souza D.S., Miguel-Dos-Santos R., Rabelo T.K., Vasconcelos C.M.L., Navia-Pelaez J.M., Jesus I.C.G., Silva-Neto J.A.D., Lauton-Santos S., Capettini L., et al. Resistance exercise mediates remote ischemic preconditioning by limiting cardiac eNOS uncoupling. J. Mol. Cell. Cardiol. 2018;125:61–72. doi: 10.1016/j.yjmcc.2018.10.016.
    1. Suvorava T., Nagy N., Pick S., Lieven O., Ruther U., Dao V.T., Fischer J.W., Weber M., Kojda G. Impact of eNOS-dependent oxidative stress on endothelial function and neointima formation. Antioxid. Redox Signal. 2015;23:711–723. doi: 10.1089/ars.2014.6059.
    1. Suvorava T., Pick S., Kojda G. Selective impairment of blood pressure reduction by endothelial nitric oxide synthase dimer destabilization in mice. J. Hypertens. 2017;35:76–88. doi: 10.1097/HJH.0000000000001127.
    1. Benson M.A., Batchelor H., Chuaiphichai S., Bailey J., Zhu H., Stuehr D.J., Bhattacharya S., Channon K.M., Crabtree M.J. A pivotal role for tryptophan 447 in enzymatic coupling of human endothelial nitric oxide synthase (eNOS): Effects on tetrahydrobiopterin-dependent catalysis and eNOS dimerization. J. Biol. Chem. 2013;288:29836–29845. doi: 10.1074/jbc.M113.493023.
    1. Daiber A., Frein D., Namgaladze D., Ullrich V. Oxidation and nitrosation in the nitrogen monoxide/superoxide system. J. Biol. Chem. 2002;277:11882–11888. doi: 10.1074/jbc.M111988200.
    1. Campos-Mota G.P., Navia-Pelaez J.M., Araujo-Souza J.C., Stergiopulos N., Capettini L.S.A. Role of ERK1/2 activation and nNOS uncoupling on endothelial dysfunction induced by lysophosphatidylcholine. Atherosclerosis. 2017;258:108–118. doi: 10.1016/j.atherosclerosis.2016.11.022.
    1. Chen C.A., Wang T.Y., Varadharaj S., Reyes L.A., Hemann C., Talukder M.A., Chen Y.R., Druhan L.J., Zweier J.L. S-glutathionylation uncouples eNOS and regulates its cellular and vascular function. Nature. 2010;468:1115–1118. doi: 10.1038/nature09599.
    1. Zweier J.L., Chen C.A., Druhan L.J. S-glutathionylation reshapes our understanding of endothelial nitric oxide synthase uncoupling and nitric oxide/reactive oxygen species-mediated signaling. Antioxid. Redox Signal. 2011;14:1769–1775. doi: 10.1089/ars.2011.3904.
    1. Oelze M., Knorr M., Kroller-Schon S., Kossmann S., Gottschlich A., Rummler R., Schuff A., Daub S., Doppler C., Kleinert H., et al. Chronic therapy with isosorbide-5-mononitrate causes endothelial dysfunction, oxidative stress, and a marked increase in vascular endothelin-1 expression. Eur. Heart J. 2013;34:3206–3216. doi: 10.1093/eurheartj/ehs100.
    1. Kroller-Schon S., Steven S., Kossmann S., Scholz A., Daub S., Oelze M., Xia N., Hausding M., Mikhed Y., Zinssius E., et al. Molecular mechanisms of the crosstalk between mitochondria and NADPH oxidase through reactive oxygen species-studies in white blood cells and in animal models. Antioxid. Redox Signal. 2014;20:247–266. doi: 10.1089/ars.2012.4953.
    1. Oelze M., Kroller-Schon S., Steven S., Lubos E., Doppler C., Hausding M., Tobias S., Brochhausen C., Li H., Torzewski M., et al. Glutathione peroxidase-1 deficiency potentiates dysregulatory modifications of endothelial nitric oxide synthase and vascular dysfunction in aging. Hypertension. 2014;63:390–396. doi: 10.1161/HYPERTENSIONAHA.113.01602.
    1. Speer T., Owala F.O., Holy E.W., Zewinger S., Frenzel F.L., Stahli B.E., Razavi M., Triem S., Cvija H., Rohrer L., et al. Carbamylated low-density lipoprotein induces endothelial dysfunction. Eur. Heart J. 2014;35:3021–3032. doi: 10.1093/eurheartj/ehu111.
    1. Wu F., Szczepaniak W.S., Shiva S., Liu H., Wang Y., Wang L., Wang Y., Kelley E.E., Chen A.F., Gladwin M.T., et al. Nox2-dependent glutathionylation of endothelial NOS leads to uncoupled superoxide production and endothelial barrier dysfunction in acute lung injury. Am. J. Physiol.-Lung Cell. Mol. Physiol. 2014;307:L987–L997. doi: 10.1152/ajplung.00063.2014.
    1. Van Deel E.D., Octavia Y., de Boer M., Juni R.P., Tempel D., van Haperen R., de Crom R., Moens A.L., Merkus D., Duncker D.J. Normal and high eNOS levels are detrimental in both mild and severe cardiac pressure-overload. J. Mol. Cell. Cardiol. 2015;88:145–154. doi: 10.1016/j.yjmcc.2015.10.001.
    1. Musicki B., Hannan J.L., Lagoda G., Bivalacqua T.J., Burnett A.L. Mechanistic link between erectile dysfunction and systemic endothelial dysfunction in type 2 diabetic rats. Andrology. 2016;4:977–983. doi: 10.1111/andr.12218.
    1. Kroller-Schon S., Daiber A., Steven S., Oelze M., Frenis K., Kalinovic S., Heimann A., Schmidt F.P., Pinto A., Kvandova M., et al. Crucial role for nox2 and sleep deprivation in aircraft noise-induced vascular and cerebral oxidative stress, inflammation, and gene regulation. Eur. Heart J. 2018;39:3528–3539. doi: 10.1093/eurheartj/ehy333.
    1. Munzel T., Daiber A., Steven S., Tran L.P., Ullmann E., Kossmann S., Schmidt F.P., Oelze M., Xia N., Li H., et al. Effects of noise on vascular function, oxidative stress, and inflammation: Mechanistic insight from studies in mice. Eur. Heart J. 2017;38:2838–2849. doi: 10.1093/eurheartj/ehx081.
    1. Van Deel E.D., Octavia Y., de Waard M.C., de Boer M., Duncker D.J. Exercise training has contrasting effects in myocardial infarction and pressure overload due to divergent endothelial nitric oxide synthase regulation. Int. J. Mol. Sci. 2018;19:1968. doi: 10.3390/ijms19071968.
    1. Du Y., Navab M., Shen M., Hill J., Pakbin P., Sioutas C., Hsiai T.K., Li R. Ambient ultrafine particles reduce endothelial nitric oxide production via S-glutathionylation of eNOS. Biochem. Biophys. Res. Commun. 2013;436:462–466. doi: 10.1016/j.bbrc.2013.05.127.
    1. De Pascali F., Hemann C., Samons K., Chen C.A., Zweier J.L. Hypoxia and reoxygenation induce endothelial nitric oxide synthase uncoupling in endothelial cells through tetrahydrobiopterin depletion and S-glutathionylation. Biochemistry. 2014;53:3679–3688. doi: 10.1021/bi500076r.
    1. Chen C.A., De Pascali F., Basye A., Hemann C., Zweier J.L. Redox modulation of endothelial nitric oxide synthase by glutaredoxin-1 through reversible oxidative post-translational modification. Biochemistry. 2013;52:6712–6723. doi: 10.1021/bi400404s.
    1. Shang Q., Bao L., Guo H., Hao F., Luo Q., Chen J., Guo C. Contribution of glutaredoxin-1 to S-glutathionylation of endothelial nitric oxide synthase for mesenteric nitric oxide generation in experimental necrotizing enterocolitis. Transl. Res. 2017;188:92–105. doi: 10.1016/j.trsl.2016.01.004.
    1. Li X., Li X., Shang Q., Gao Z., Hao F., Guo H., Guo C. Fecal microbiota transplantation (FMT) could reverse the severity of experimental necrotizing enterocolitis (NEC) via oxidative stress modulation. Free Radic. Biol. Med. 2017;108:32–43. doi: 10.1016/j.freeradbiomed.2017.03.011.
    1. Espinosa-Diez C., Miguel V., Vallejo S., Sanchez F.J., Sandoval E., Blanco E., Cannata P., Peiro C., Sanchez-Ferrer C.F., Lamas S. Role of glutathione biosynthesis in endothelial dysfunction and fibrosis. Redox Biol. 2018;14:88–99. doi: 10.1016/j.redox.2017.08.019.
    1. Crabtree M.J., Brixey R., Batchelor H., Hale A.B., Channon K.M. Integrated redox sensor and effector functions for tetrahydrobiopterin- and glutathionylation-dependent endothelial nitric-oxide synthase uncoupling. J. Biol. Chem. 2013;288:561–569. doi: 10.1074/jbc.M112.415992.
    1. Idigo W.O., Reilly S., Zhang M.H., Zhang Y.H., Jayaram R., Carnicer R., Crabtree M.J., Balligand J.L., Casadei B. Regulation of endothelial nitric-oxide synthase (NOS) S-glutathionylation by neuronal NOS: Evidence of a functional interaction between myocardial constitutive NOS isoforms. J. Biol. Chem. 2012;287:43665–43673. doi: 10.1074/jbc.M112.412031.
    1. Dimmeler S., Fleming I., Fisslthaler B., Hermann C., Busse R., Zeiher A.M. Activation of nitric oxide synthase in endothelial cells by AKT-dependent phosphorylation. Nature. 1999;399:601–605. doi: 10.1038/21224.
    1. Loot A.E., Schreiber J.G., Fisslthaler B., Fleming I. Angiotensin ii impairs endothelial function via tyrosine phosphorylation of the endothelial nitric oxide synthase. J. Exp. Med. 2009;206:2889–2896. doi: 10.1084/jem.20090449.
    1. Fleming I., Fisslthaler B., Dimmeler S., Kemp B.E., Busse R. Phosphorylation of Thr(495) regulates Ca2+/calmodulin-dependent endothelial nitric oxide synthase activity. Circ. Res. 2001;88:e68–e75. doi: 10.1161/hh1101.092677.
    1. Lin M.I., Fulton D., Babbitt R., Fleming I., Busse R., Pritchard K.A., Jr., Sessa W.C. Phosphorylation of threonine 497 in endothelial nitric-oxide synthase coordinates the coupling of L-arginine metabolism to efficient nitric oxide production. J. Biol. Chem. 2003;278:44719–44726. doi: 10.1074/jbc.M302836200.
    1. Matsubara M., Hayashi N., Jing T., Titani K. Regulation of endothelial nitric oxide synthase by protein kinase C. J. Biochem. 2003;133:773–781. doi: 10.1093/jb/mvg099.
    1. Rathore R., Zheng Y.M., Niu C.F., Liu Q.H., Korde A., Ho Y.S., Wang Y.X. Hypoxia activates NADPH oxidase to increase [ROS]i and [Ca2+]i through the mitochondrial ROS-PKCε signaling axis in pulmonary artery smooth muscle cells. Free Radic. Biol. Med. 2008;45:1223–1231. doi: 10.1016/j.freeradbiomed.2008.06.012.
    1. Lin D., Takemoto D.J. Oxidative activation of protein kinase Cγ through the C1 domain. Effects on gap junctions. J. Biol. Chem. 2005;280:13682–13693. doi: 10.1074/jbc.M407762200.
    1. Signorello M.G., Segantin A., Passalacqua M., Leoncini G. Homocysteine decreases platelet NO level via protein kinase C activation. Nitric Oxide. 2009;20:104–113. doi: 10.1016/j.niox.2008.11.005.
    1. Singh U., Devaraj S., Vasquez-Vivar J., Jialal I. C-reactive protein decreases endothelial nitric oxide synthase activity via uncoupling. J. Mol. Cell. Cardiol. 2007;43:780–791. doi: 10.1016/j.yjmcc.2007.08.015.
    1. Lenasi H., Kohlstedt K., Fichtlscherer B., Mulsch A., Busse R., Fleming I. Amlodipine activates the endothelial nitric oxide synthase by altering phosphorylation on Ser1177 and Thr495. Cardiovasc. Res. 2003;59:844–853. doi: 10.1016/S0008-6363(03)00505-4.
    1. Barauna V.G., Mantuan P.R., Magalhaes F.C., Campos L.C., Krieger J.E. AT1 receptor blocker potentiates shear-stress induced nitric oxide production via modulation of eNOS phosphorylation of residues Thr495 and Ser1177. Biochem. Biophys. Res. Commun. 2013;441:713–719. doi: 10.1016/j.bbrc.2013.10.108.
    1. Knorr M., Hausding M., Kroller-Schuhmacher S., Steven S., Oelze M., Heeren T., Scholz A., Gori T., Wenzel P., Schulz E., et al. Nitroglycerin-induced endothelial dysfunction and tolerance involve adverse phosphorylation and S-glutathionylation of endothelial nitric oxide synthase: Beneficial effects of therapy with the AT1 receptor blocker telmisartan. Arterioscler. Thromb. Vasc. Biol. 2011;31:2223–2231. doi: 10.1161/ATVBAHA.111.232058.
    1. Almansob M.A., Xu B., Zhou L., Hu X.X., Chen W., Chang F.J., Ci H.B., Yao J.P., Xu Y.Q., Yao F.J., et al. Simvastatin reduces myocardial injury undergoing noncoronary artery cardiac surgery: A randomized controlled trial. Arterioscler. Thromb. Vasc. Biol. 2012;32:2304–2313. doi: 10.1161/ATVBAHA.112.252098.
    1. Yang L., Jia Z., Yang L., Zhu M., Zhang J., Liu J., Wu P., Tian W., Li J., Qi Z., et al. Exercise protects against chronic beta-adrenergic remodeling of the heart by activation of endothelial nitric oxide synthase. PLoS ONE. 2014;9:e96892.
    1. Calvert J.W., Condit M.E., Aragon J.P., Nicholson C.K., Moody B.F., Hood R.L., Sindler A.L., Gundewar S., Seals D.R., Barouch L.A., et al. Exercise protects against myocardial ischemia-reperfusion injury via stimulation of β3-adrenergic receptors and increased nitric oxide signaling: Role of nitrite and nitrosothiols. Circ. Res. 2011;108:1448–1458. doi: 10.1161/CIRCRESAHA.111.241117.
    1. Guterbaum T.J., Braunstein T.H., Fossum A., Holstein-Rathlou N.H., Torp-Pedersen C.T., Dominguez H. Endothelial nitric oxide synthase phosphorylation at threonine 495 and mitochondrial reactive oxygen species formation in response to a high H2O2 concentration. J. Vasc. Res. 2013;50:410–420. doi: 10.1159/000354225.
    1. Carlstrom M., Liu M., Yang T., Zollbrecht C., Huang L., Peleli M., Borniquel S., Kishikawa H., Hezel M., Persson A.E., et al. Cross-talk between nitrate-nitrite-NO and NO synthase pathways in control of vascular NO homeostasis. Antioxid. Redox Signal. 2015;23:295–306. doi: 10.1089/ars.2013.5481.
    1. Boger R.H. Association of asymmetric dimethylarginine and endothelial dysfunction. Clin. Chem. Lab. Med. 2003;41:1467–1472. doi: 10.1515/CCLM.2003.225.
    1. Sydow K., Munzel T. ADMA and oxidative stress. Atheroscler. Suppl. 2003;4:41–51. doi: 10.1016/S1567-5688(03)00033-3.
    1. Schnabel R., Blankenberg S., Lubos E., Lackner K.J., Rupprecht H.J., Espinola-Klein C., Jachmann N., Post F., Peetz D., Bickel C., et al. Asymmetric dimethylarginine and the risk of cardiovascular events and death in patients with coronary artery disease: Results from The AtheroGene Study. Circ. Res. 2005;97:e53–e59. doi: 10.1161/01.RES.0000181286.44222.61.
    1. Boger R.H. When the endothelium cannot say ‘NO’ anymore. ADMA, an endogenous inhibitor of NO synthase, promotes cardiovascular disease. Eur. Heart J. 2003;24:1901–1902. doi: 10.1016/j.ehj.2003.08.010.
    1. Tousoulis D., Papageorgiou N., Androulakis E., Siasos G., Latsios G., Tentolouris K., Stefanadis C. Diabetes mellitus-associated vascular impairment: Novel circulating biomarkers and therapeutic approaches. J. Am. Coll. Cardiol. 2013;62:667–676. doi: 10.1016/j.jacc.2013.03.089.
    1. Zhou R., Ma P., Xiong A., Xu Y., Wang Y., Xu Q. Protective effects of low-dose rosuvastatin on isoproterenol-induced chronic heart failure in rats by regulation of DDAH-ADMA-NO pathway. Cardiovasc. Ther. 2017;35:e12241. doi: 10.1111/1755-5922.12241.
    1. Hsu C.P., Zhao J.F., Lin S.J., Shyue S.K., Guo B.C., Lu T.M., Lee T.S. Asymmetric dimethylarginine limits the efficacy of simvastatin activating endothelial nitric oxide synthase. J. Am. Heart Assoc. 2016;5:e003327. doi: 10.1161/JAHA.116.003327.
    1. Lin Y., Feng M., Lu C.W., Lei Y.P., He Z.M., Xiong Y. Preservation of vascular DDAH activity contributes to the protection of captopril against endothelial dysfunction in hyperlipidemic rabbits. Eur. J. Pharmacol. 2017;798:43–48. doi: 10.1016/j.ejphar.2017.01.041.
    1. Bode-Boger S.M., Scalera F., Ignarro L.J. The L-arginine paradox: Importance of the L-arginine/asymmetrical dimethylarginine ratio. Pharmacol. Ther. 2007;114:295–306. doi: 10.1016/j.pharmthera.2007.03.002.
    1. Lass A., Suessenbacher A., Wolkart G., Mayer B., Brunner F. Functional and analytical evidence for scavenging of oxygen radicals by L-arginine. Mol. Pharmacol. 2002;61:1081–1088. doi: 10.1124/mol.61.5.1081.
    1. Closs E.I., Ostad M.A., Simon A., Warnholtz A., Jabs A., Habermeier A., Daiber A., Forstermann U., Munzel T. Impairment of the extrusion transporter for asymmetric dimethyl-L-arginine: A novel mechanism underlying vasospastic angina. Biochem. Biophys. Res. Commun. 2012;423:218–223. doi: 10.1016/j.bbrc.2012.05.044.
    1. Watson C.P., Pazarentzos E., Fidanboylu M., Padilla B., Brown R., Thomas S.A. The transporter and permeability interactions of asymmetric dimethylarginine (ADMA) and L-arginine with the human blood-brain barrier in vitro. Brain Res. 2016;1648:232–242. doi: 10.1016/j.brainres.2016.07.026.
    1. Speranza L., Franceschelli S., D’Orazio N., Gaeta R., Bucciarelli T., Felaco M., Grilli A., Riccioni G. The biological effect of pharmacological treatment on dimethylaminohydrolases (DDAH-1) and cationic amino acid transporter-1 (CAT-1) expression in patients with acute congestive heart failure. Microvasc. Res. 2011;82:391–396. doi: 10.1016/j.mvr.2011.06.003.
    1. Yang Z., Ming X.F. Arginase: The emerging therapeutic target for vascular oxidative stress and inflammation. Front. Immunol. 2013;4:149. doi: 10.3389/fimmu.2013.00149.
    1. Pitt B., Stier C.T., Jr., Rajagopalan S. Mineralocorticoid receptor blockade: New insights into the mechanism of action in patients with cardiovascular disease. J. Renin Angiotensin Aldosterone Syst. 2003;4:164–168. doi: 10.3317/jraas.2003.025.
    1. Mehler P.S., Coll J.R., Estacio R., Esler A., Schrier R.W., Hiatt W.R. Intensive blood pressure control reduces the risk of cardiovascular events in patients with peripheral arterial disease and type 2 diabetes. Circulation. 2003;107:753–756. doi: 10.1161/01.CIR.0000049640.46039.52.
    1. Kintscher U., Bramlage P., Paar W.D., Thoenes M., Unger T. Irbesartan for the treatment of hypertension in patients with the metabolic syndrome: A sub analysis of the Treat to Target post authorization survey. Prospective observational, two armed study in 14,200 patients. Cardiovasc. Diabetol. 2007;6:12. doi: 10.1186/1475-2840-6-12.
    1. Parving H.H., Brenner B.M., McMurray J.J., de Zeeuw D., Haffner S.M., Solomon S.D., Chaturvedi N., Ghadanfar M., Weissbach N., Xiang Z., et al. Aliskiren trial in type 2 diabetes using cardio-renal endpoints (ALTITUDE): Rationale and study design. Nephrol. Dial. Transplant. 2009;24:1663–1671. doi: 10.1093/ndt/gfn721.
    1. Koh K.K., Lim S., Choi H., Lee Y., Han S.H., Lee K., Oh P.C., Sakuma I., Shin E.K., Quon M.J. Combination pravastatin and valsartan treatment has additive beneficial effects to simultaneously improve both metabolic and cardiovascular phenotypes beyond that of monotherapy with either drug in patients with primary hypercholesterolemia. Diabetes. 2013;62:3547–3552. doi: 10.2337/db13-0566.
    1. Patel T.N., Shishehbor M.H., Bhatt D.L. A review of high-dose statin therapy: Targeting cholesterol and inflammation in atherosclerosis. Eur. Heart J. 2007;28:664–672. doi: 10.1093/eurheartj/ehl445.
    1. Goodfriend T.L., Elliott M.E., Catt K.J. Angiotensin receptors and their antagonists. N. Engl. J. Med. 1996;334:1649–1654. doi: 10.1056/NEJM199606203342507.
    1. Steven S., Munzel T., Daiber A. Exploiting the pleiotropic antioxidant effects of established drugs in cardiovascular disease. Int. J. Mol. Sci. 2015;16:18185–18223. doi: 10.3390/ijms160818185.
    1. Hibbert B., Simard T., Ramirez F.D., Pourdjabbar A., Raizman J.E., Maze R., Wilson K.R., Hawken S., O’Brien E.R. The effect of statins on circulating endothelial progenitor cells in humans: A systematic review. J. Cardiovasc. Pharmacol. 2013;62:491–496. doi: 10.1097/FJC.0b013e3182a4027f.
    1. Broeders M.A., Doevendans P.A., Bekkers B.C., Bronsaer R., van Gorsel E., Heemskerk J.W., Egbrink M.G., van Breda E., Reneman R.S., van Der Zee R. Nebivolol: A third-generation beta-blocker that augments vascular nitric oxide release: Endothelial β2-adrenergic receptor-mediated nitric oxide production. Circulation. 2000;102:677–684. doi: 10.1161/01.CIR.102.6.677.
    1. Tzemos N., Lim P.O., MacDonald T.M. Nebivolol reverses endothelial dysfunction in essential hypertension: A randomized, double-blind, crossover study. Circulation. 2001;104:511–514. doi: 10.1161/hc3001.094207.
    1. Oelze M., Daiber A., Brandes R.P., Hortmann M., Wenzel P., Hink U., Schulz E., Mollnau H., von Sandersleben A., Kleschyov A.L., et al. Nebivolol inhibits superoxide formation by NADPH oxidase and endothelial dysfunction in angiotensin II-treated rats. Hypertension. 2006;48:677–684. doi: 10.1161/01.HYP.0000239207.82326.29.
    1. Sorrentino S.A., Doerries C., Manes C., Speer T., Dessy C., Lobysheva I., Mohmand W., Akbar R., Bahlmann F., Besler C., et al. Nebivolol exerts beneficial effects on endothelial function, early endothelial progenitor cells, myocardial neovascularization, and left ventricular dysfunction early after myocardial infarction beyond conventional beta1-blockade. J. Am. Coll. Cardiol. 2011;57:601–611. doi: 10.1016/j.jacc.2010.09.037.
    1. Magee L.A., Abalos E., von Dadelszen P., Sibai B., Easterling T., Walkinshaw S., Group C.S. How to manage hypertension in pregnancy effectively. Br. J. Clin. Pharmacol. 2011;72:394–401. doi: 10.1111/j.1365-2125.2011.04002.x.
    1. Taylor A.L., Lindenfeld J., Ziesche S., Walsh M.N., Mitchell J.E., Adams K., Tam S.W., Ofili E., Sabolinski M.L., Worcel M., et al. Outcomes by gender in the African-American heart failure trial. J. Am. Coll. Cardiol. 2006;48:2263–2267. doi: 10.1016/j.jacc.2006.06.020.
    1. Taylor A.L., Ziesche S., Yancy C., Carson P., D’Agostino R., Jr., Ferdinand K., Taylor M., Adams K., Sabolinski M., Worcel M., et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N. Engl. J. Med. 2004;351:2049–2057. doi: 10.1056/NEJMoa042934.
    1. Munzel T., Meinertz T., Tebbe U., Schneider H.T., Stalleicken D., Wargenau M., Gori T., Klingmann I., Investigators C.S. Efficacy of the long-acting nitro vasodilator pentaerithrityl tetranitrate in patients with chronic stable angina pectoris receiving anti-anginal background therapy with beta-blockers: A 12-week, randomized, double-blind, placebo-controlled trial. Eur. Heart J. 2014;35:895–903. doi: 10.1093/eurheartj/eht384.
    1. Oberle S., Abate A., Grosser N., Vreman H.J., Dennery P.A., Schneider H.T., Stalleicken D., Schroder H. Heme oxygenase-1 induction may explain the antioxidant profile of pentaerythrityl trinitrate. Biochem. Biophys. Res. Commun. 2002;290:1539–1544. doi: 10.1006/bbrc.2002.6379.
    1. Wenzel P., Oelze M., Coldewey M., Hortmann M., Seeling A., Hink U., Mollnau H., Stalleicken D., Weiner H., Lehmann J., et al. Heme oxygenase-1: A novel key player in the development of tolerance in response to organic nitrates. Arterioscler. Thromb. Vasc. Biol. 2007;27:1729–1735. doi: 10.1161/ATVBAHA.107.143909.
    1. Schuhmacher S., Oelze M., Bollmann F., Kleinert H., Otto C., Heeren T., Steven S., Hausding M., Knorr M., Pautz A., et al. Vascular dysfunction in experimental diabetes is improved by pentaerithrityl tetranitrate but not isosorbide-5-mononitrate therapy. Diabetes. 2011;60:2608–2616. doi: 10.2337/db10-1395.
    1. Boswell-Smith V., Spina D., Page C.P. Phosphodiesterase inhibitors. Br. J. Pharmacol. 2006;147(Suppl. 1):S252–S257. doi: 10.1038/sj.bjp.0706495.
    1. Evgenov O.V., Pacher P., Schmidt P.M., Hasko G., Schmidt H.H., Stasch J.P. NO-independent stimulators and activators of soluble guanylate cyclase: Discovery and therapeutic potential. Nat. Rev. Drug Discov. 2006;5:755–768. doi: 10.1038/nrd2038.
    1. Schuhmacher S., Wenzel P., Schulz E., Oelze M., Mang C., Kamuf J., Gori T., Jansen T., Knorr M., Karbach S., et al. Pentaerythritol tetranitrate improves angiotensin II-induced vascular dysfunction via induction of heme oxygenase-1. Hypertension. 2010;55:897–904. doi: 10.1161/HYPERTENSIONAHA.109.149542.
    1. Wenzel P., Schulz E., Oelze M., Muller J., Schuhmacher S., Alhamdani M.S., Debrezion J., Hortmann M., Reifenberg K., Fleming I., et al. AT1-receptor blockade by telmisartan upregulates GTP-cyclohydrolase I and protects eNOS in diabetic rats. Free Radic. Biol. Med. 2008;45:619–626. doi: 10.1016/j.freeradbiomed.2008.05.009.
    1. Wenzel P., Daiber A., Oelze M., Brandt M., Closs E., Xu J., Thum T., Bauersachs J., Ertl G., Zou M.H., et al. Mechanisms underlying recoupling of eNOS by HMG-CoA reductase inhibition in a rat model of streptozotocin-induced diabetes mellitus. Atherosclerosis. 2008;198:65–76. doi: 10.1016/j.atherosclerosis.2007.10.003.
    1. Heitzer T., Brockhoff C., Mayer B., Warnholtz A., Mollnau H., Henne S., Meinertz T., Munzel T. Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers: Evidence for a dysfunctional nitric oxide synthase. Circ. Res. 2000;86:E36–E41. doi: 10.1161/01.RES.86.2.e36.
    1. Heitzer T., Krohn K., Albers S., Meinertz T. Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with type ii diabetes mellitus. Diabetologia. 2000;43:1435–1438. doi: 10.1007/s001250051551.
    1. Antoniades C., Shirodaria C., Warrick N., Cai S., de Bono J., Lee J., Leeson P., Neubauer S., Ratnatunga C., Pillai R., et al. 5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: Effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. Circulation. 2006;114:1193–1201. doi: 10.1161/CIRCULATIONAHA.106.612325.
    1. Gori T., Burstein J.M., Ahmed S., Miner S.E., Al-Hesayen A., Kelly S., Parker J.D. Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance: A human in vivo study. Circulation. 2001;104:1119–1123. doi: 10.1161/hc3501.095358.
    1. De Maria R., Campolo J., Frontali M., Taroni F., Federico A., Inzitari D., Tavani A., Romano S., Puca E., Orzi F., et al. Effects of sapropterin on endothelium-dependent vasodilation in patients with CADASIL: A randomized controlled trial. Stroke. 2014;45:2959–2966. doi: 10.1161/STROKEAHA.114.005937.
    1. Reverter E., Mesonero F., Seijo S., Martinez J., Abraldes J.G., Penas B., Berzigotti A., Deulofeu R., Bosch J., Albillos A., et al. Effects of sapropterin on portal and systemic hemodynamics in patients with cirrhosis and portal hypertension: A bicentric double-blind placebo-controlled study. Am. J. Gastroenterol. 2015;110:985–992. doi: 10.1038/ajg.2015.185.
    1. Jeong J.H., Lee N., Tucker M.A., Rodriguez-Miguelez P., Looney J., Thomas J., Derella C.C., El-Marakby A.A., Musall J.B., Sullivan J.C., et al. Tetrahydrobiopterin improves endothelial function in patients with cystic fibrosis. J. Appl. Physiol. 2018 doi: 10.1152/japplphysiol.00629.2018.
    1. Machin D.R., Clifton H.L., Richardson R.S., Wray D.W., Donato A.J., Frech T.M. Acute oral tetrahydrobiopterin administration ameliorates endothelial dysfunction in systemic sclerosis. Clin. Exp. Rheumatol. 2017;35(Suppl. 106):167–172.
    1. Maki-Petaja K.M., Day L., Cheriyan J., Hall F.C., Ostor A.J., Shenker N., Wilkinson I.B. Tetrahydrobiopterin supplementation improves endothelial function but does not alter aortic stiffness in patients with rheumatoid arthritis. J. Am. Heart Assoc. 2016;5:e002762. doi: 10.1161/JAHA.115.002762.
    1. McCarty M.F. Supplementation with phycocyanobilin, citrulline, taurine, and supranutritional doses of folic acid and biotin-potential for preventing or slowing the progression of diabetic complications. Healthcare. 2017;5:15. doi: 10.3390/healthcare5010015.
    1. Fraccarollo D., Widder J.D., Galuppo P., Thum T., Tsikas D., Hoffmann M., Ruetten H., Ertl G., Bauersachs J. Improvement in left ventricular remodeling by the endothelial nitric oxide synthase enhancer AVE9488 after experimental myocardial infarction. Circulation. 2008;118:818–827. doi: 10.1161/CIRCULATIONAHA.107.717702.
    1. Westermann D., Riad A., Richter U., Jager S., Savvatis K., Schuchardt M., Bergmann N., Tolle M., Nagorsen D., Gotthardt M., et al. Enhancement of the endothelial no synthase attenuates experimental diastolic heart failure. Basic Res. Cardiol. 2009;104:499–509. doi: 10.1007/s00395-009-0014-6.
    1. Crabtree M.J., Tatham A.L., Al-Wakeel Y., Warrick N., Hale A.B., Cai S., Channon K.M., Alp N.J. Quantitative regulation of intracellular endothelial nitric-oxide synthase (eNOS) coupling by both tetrahydrobiopterin-eNOS stoichiometry and biopterin redox status: Insights from cells with TET-regulated GTP cyclohydrolase I expression. J. Biol. Chem. 2009;284:1136–1144. doi: 10.1074/jbc.M805403200.
    1. Li H., Witte K., August M., Brausch I., Godtel-Armbrust U., Habermeier A., Closs E.I., Oelze M., Munzel T., Forstermann U. Reversal of endothelial nitric oxide synthase uncoupling and up-regulation of endothelial nitric oxide synthase expression lowers blood pressure in hypertensive rats. J. Am. Coll. Cardiol. 2006;47:2536–2544. doi: 10.1016/j.jacc.2006.01.071.
    1. Sasaki K., Heeschen C., Aicher A., Ziebart T., Honold J., Urbich C., Rossig L., Koehl U., Koyanagi M., Mohamed A., et al. Ex vivo pretreatment of bone marrow mononuclear cells with endothelial NO synthase enhancer AVE9488 enhances their functional activity for cell therapy. Proc. Natl. Acad. Sci. USA. 2006;103:14537–14541. doi: 10.1073/pnas.0604144103.
    1. Frantz S., Adamek A., Fraccarollo D., Tillmanns J., Widder J.D., Dienesch C., Schafer A., Podolskaya A., Held M., Ruetten H., et al. The eNOS enhancer AVE 9488: A novel cardioprotectant against ischemia reperfusion injury. Basic Res. Cardiol. 2009;104:773–779. doi: 10.1007/s00395-009-0041-3.
    1. Riad A., Westermann D., Van Linthout S., Mohr Z., Uyulmaz S., Becher P.M., Rutten H., Wohlfart P., Peters H., Schultheiss H.P., et al. Enhancement of endothelial nitric oxide synthase production reverses vascular dysfunction and inflammation in the hindlimbs of a rat model of diabetes. Diabetologia. 2008;51:2325–2332. doi: 10.1007/s00125-008-1159-9.
    1. Yang Q., Xue H.M., Wong W.T., Tian X.Y., Huang Y., Tsui S.K., Ng P.K., Wohlfart P., Li H., Xia N., et al. AVE3085, an enhancer of endothelial nitric oxide synthase, restores endothelial function and reduces blood pressure in spontaneously hypertensive rats. Br. J. Pharmacol. 2011;163:1078–1085. doi: 10.1111/j.1476-5381.2011.01308.x.
    1. Cheang W.S., Wong W.T., Tian X.Y., Yang Q., Lee H.K., He G.W., Yao X., Huang Y. Endothelial nitric oxide synthase enhancer reduces oxidative stress and restores endothelial function in db/db mice. Cardiovasc. Res. 2011;92:267–275. doi: 10.1093/cvr/cvr233.
    1. Chen Y., Chen C., Feng C., Tang A., Ma Y., He X., Li Y., He J., Dong Y. AVE 3085, a novel endothelial nitric oxide synthase enhancer, attenuates cardiac remodeling in mice through the Smad signaling pathway. Arch. Biochem. Biophys. 2015;570:8–13. doi: 10.1016/j.abb.2015.02.020.
    1. Hou H.T., Wang J., Zhang X., Wang Z.Q., Chen T.N., Zhang J.L., Yang Q., He G.W. Endothelial nitric oxide synthase enhancer AVE3085 reverses endothelial dysfunction induced by homocysteine in human internal mammary arteries. Nitric Oxide. 2018;81:21–27. doi: 10.1016/j.niox.2018.10.001.
    1. Schafer A., Fraccarollo D., Widder J., Eigenthaler M., Ertl G., Bauersachs J. Inhibition of platelet activation in rats with severe congestive heart failure by a novel endothelial nitric oxide synthase transcription enhancer. Eur. J. Heart Fail. 2009;11:336–341. doi: 10.1093/eurjhf/hfp005.
    1. Wallerath T., Li H., Godtel-Ambrust U., Schwarz P.M., Forstermann U. A blend of polyphenolic compounds explains the stimulatory effect of red wine on human endothelial no synthase. Nitric Oxide. 2005;12:97–104. doi: 10.1016/j.niox.2004.12.004.
    1. Xia N., Forstermann U., Li H. Resveratrol and endothelial nitric oxide. Molecules. 2014;19:16102–16121. doi: 10.3390/molecules191016102.
    1. Matouk C.C., Marsden P.A. Epigenetic regulation of vascular endothelial gene expression. Circ. Res. 2008;102:873–887. doi: 10.1161/CIRCRESAHA.107.171025.
    1. Chan Y., Fish J.E., D’Abreo C., Lin S., Robb G.B., Teichert A.M., Karantzoulis-Fegaras F., Keightley A., Steer B.M., Marsden P.A. The cell-specific expression of endothelial nitric-oxide synthase: A role for DNA methylation. J. Biol. Chem. 2004;279:35087–35100. doi: 10.1074/jbc.M405063200.
    1. Fish J.E., Matouk C.C., Rachlis A., Lin S., Tai S.C., D’Abreo C., Marsden P.A. The expression of endothelial nitric-oxide synthase is controlled by a cell-specific histone code. J. Biol. Chem. 2005;280:24824–24838. doi: 10.1074/jbc.M502115200.
    1. Gan Y., Shen Y.H., Wang J., Wang X., Utama B., Wang J., Wang X.L. Role of histone deacetylation in cell-specific expression of endothelial nitric-oxide synthase. J. Biol. Chem. 2005;280:16467–16475. doi: 10.1074/jbc.M412960200.
    1. Gluckman P.D., Hanson M.A., Buklijas T., Low F.M., Beedle A.S. Epigenetic mechanisms that underpin metabolic and cardiovascular diseases. Nat. Rev. Endocrinol. 2009;5:401–408. doi: 10.1038/nrendo.2009.102.
    1. Krause B.J., Costello P.M., Munoz-Urrutia E., Lillycrop K.A., Hanson M.A., Casanello P. Role of DNA methyltransferase 1 on the altered eNOS expression in human umbilical endothelium from intrauterine growth restricted fetuses. Epigenetics. 2013;8:944–952. doi: 10.4161/epi.25579.
    1. Herrera E.A., Cifuentes-Zuniga F., Figueroa E., Villanueva C., Hernandez C., Alegria R., Arroyo-Jousse V., Penaloza E., Farias M., Uauy R., et al. N-acetylcysteine, a glutathione precursor, reverts vascular dysfunction and endothelial epigenetic programming in intrauterine growth restricted guinea pigs. J. Physiol. 2017;595:1077–1092. doi: 10.1113/JP273396.
    1. Grandvuillemin I., Buffat C., Boubred F., Lamy E., Fromonot J., Charpiot P., Simoncini S., Sabatier F., Dignat-George F., Peyter A.C., et al. Arginase upregulation and eNOS uncoupling contribute to impaired endothelium-dependent vasodilation in a rat model of intrauterine growth restriction. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2018;315:R509–R520. doi: 10.1152/ajpregu.00354.2017.
    1. Li H., Forstermann U. Uncoupling of endothelial NO synthase in atherosclerosis and vascular disease. Curr. Opin. Pharmacol. 2013;13:161–167. doi: 10.1016/j.coph.2013.01.006.
    1. Wu Z., Siuda D., Xia N., Reifenberg G., Daiber A., Munzel T., Forstermann U., Li H. Maternal treatment of spontaneously hypertensive rats with pentaerythritol tetranitrate reduces blood pressure in female offspring. Hypertension. 2015;65:232–237. doi: 10.1161/HYPERTENSIONAHA.114.04416.

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