Plasma nesfatin-1 and DDP-4 levels in patients with coronary artery disease: Kozani study

Nikolaos P E Kadoglou, Emmanouil Korakas, Stylianos Lampropoulos, Eirini Maratou, George Kassimis, Nikolaos Patsourakos, Panagiotis Plotas, Paraskevi Moutsatsou, Vaia Lambadiari, Nikolaos P E Kadoglou, Emmanouil Korakas, Stylianos Lampropoulos, Eirini Maratou, George Kassimis, Nikolaos Patsourakos, Panagiotis Plotas, Paraskevi Moutsatsou, Vaia Lambadiari

Abstract

Background: Nesfatin-1, a novel adipokine and dipeptidyl peptidase-4 (DPP4), a mam malian serine protease, are potent factors of atherosclerosis. In the present cross-sectional study, we investigated whether the plasma nesfatin-1 and DPP4 is associated with the prevalence and severity of coronary artery disease (CAD) with and without diabetes mellitus (DM).

Methods: We consecutively enrolled a total of 240 patients with significant CAD (previous revascularization or angiographically-proven coronary artery stenosis > 50%) presented with either unstable angina (UA, N = 76) or stable chronic CAD (SCAD, N = 165). 85 patients with at least 2 classical cardiovascular risk factors but without significant CAD served as controls. The severity of CAD was assessed using coronary angiography by the Gensini score. Clinical parameters, glycemic and lipid profile, high-sensitivity CRP (hsCRP), nesfatin-1 and DPP4 levels were assayed.

Results: No differences were found for age, sex, hypertension and diabetes distribution between groups. Low nesfatin-1 levels were found in both CAD groups (UA & SCAD) with respect to controls. The difference between UA and SCAD groups was marginally non-significant. There was a significant increase of DPP4 along UA to SCAD and control groups. Differences between groups remained unchanged in non-diabetic participants. Nesfatin-1 significantly correlated to hsCRP (r = - 0.287, p = 0.036), HOMA-IR (r = - 0.587, p = 0.007) and hyperlipidemia (r = - 0.331, p = 0.034). DPP4 was significantly associated with hs-CRP (r = 0.353 p < 0.001) and FPG (r = 0.202, p = 0.020) in univariate analysis, but those correlations were lost in multiple regression analysis. There was a negative correlation between nesfatin-1 and the severity of CAD, quantified by the Gensini score (r = - 0.511, p < 0.001), but no association was found for DPP4.

Conclusions: Serum DPP4 levels are increased in patients with CAD, while serum nesfatin-1 levels have a negative association with both the incidence and the severity of CAD. These results are independent of the presence of diabetes mellitus. In addition, both peptides have a strong association with hsCRP. Trial registration ClinicalTrials.gov Identifier: NCT00306176.

Keywords: Coronary artery disease; Dipeptidyl peptidase-4; Nesfatin-1; Unstable angina.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2021. The Author(s).

References

    1. Oh IS, Shimizu H, Satoh T, Okada S, Adachi S, Inoue K, Eguchi H, Yamamoto M, Imaki T, Hashimoto K, Tsuchiya T, Monden T, Horiguchi K, Yamada M, Mori M. Identification of nesfatin-1 as a satiety molecule in the hypothalamus. Nature. 2006;443(7112):709–12. doi: 10.1038/nature05162.
    1. Schalla MA, Stengel A. Current understanding of the role of nesfatin-1. J Endocr Soc. 2018;2(10):1188–206. doi: 10.1210/js.2018-00246.
    1. Angelone T, Rocca C, Pasqua T. Nesfatin-1 in cardiovascular orchestration: from bench to bedside. Pharmacol Res. 2020;156:104766. doi: 10.1016/j.phrs.2020.104766.
    1. Dai H, Li X, He T, Wang Y, Wang Z, Wang S, Xing M, Sun W, Ding H. Decreased plasma nesfatin-1 levels in patients with acute myocardial infarction. Peptides. 2013;46:167–71. doi: 10.1016/j.peptides.2013.06.006.
    1. Serdar Kuyumcu M, Kuyumcu A, Yayla C, et al. The relationship between nesfatin-1 levels and SYNTAX score in patients with non-ST segment elevationmyocardial infarction. Acta Cardiol Sin. 2018;34:386–93.
    1. Kuyumcu MS, Kuyumcu A, Yayla C, et al. Nesfatin-1 levels in patients with slow coronary flow. Kardiol Pol. 2018;76:401–5. doi: 10.5603/KP.a2017.0210.
    1. Sivri S, Sökmen E, Çelik M, Güçlü K. Nesfatin-1 levels predict angiographic no-reflow in patients with ST-segment elevation myocardial infarction. Acta Cardiol Sin. 2020;36(4):318–25. doi: 10.6515/ACS.202007_36(4).20200207A.
    1. Ibe S, Kishimoto Y, Niki H, Saita E, Umei T, Miura K, Ikegami Y, Ohmori R, Kondo K, Momiyama Y. Associations between plasma nesfatin-1 levels and the presence and severity of coronary artery disease. Heart vessels. 2019;34(6):965–70. doi: 10.1007/s00380-018-01328-3.
    1. Matteucci E, Giampietro O. Dipeptidyl peptidase-4 (CD26): knowing the function before inhibiting the enzyme. Curr Med Chem. 2009;16:2943–51. doi: 10.2174/092986709788803114.
    1. Mentlein R, Dipeptidyl-peptidase IV. (CD26)Ðrole in the inactivation of regulatory peptides. Regul Pept. 1999;85:9–24. doi: 10.1016/S0167-0115(99)00089-0.
    1. Lamers D, Famulla S, Wronkowitz N, Hartwig S, Lehr S, Ouwens DM, et al. Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome. Diabetes. 2011;60:1917–25. doi: 10.2337/db10-1707.
    1. Deacon CF. Physiology and pharmacology of DPP-4 in glucose homeostasis and the treatment of type 2 diabetes. Front Endocrinol. 2019;10:80. doi: 10.3389/fendo.2019.00080.
    1. Zhong J, Maiseyeu A, Davis SN, Rajagopalan S. DPP4 in cardiometabolic disease: recent insights from the laboratory and clinical trials of DPP4 inhibition. Circ Res. 2015;116(8):1491–504. doi: 10.1161/CIRCRESAHA.116.305665.
    1. Angelone T, Filice E, Pasqua T, Amodio N, Galluccio M, Montesanti G, et al. Nesfatin-1 as a novel cardiac peptide: identification, functional characterization, and protection against ischemia/reperfusion injury. Cell Mol Life Sci. 2013;70(3):495–509. doi: 10.1007/s00018-012-1138-7.
    1. Mazza R, Gattuso A, Filice M, Cantafio P, Cerra MC, Angelone T. Nesfatin-1 as a new positive inotrope in the goldfish (Carassius auratus) heart, Gen. Comp Endocrinol. 2015;224:160–7. doi: 10.1016/j.ygcen.2015.08.003.
    1. Yilmaz MS, Altinbas B, Guvenc G, Erkan LG, Avsar O, Savci V, et al. The role of centrally injected nesfatin-1 on cardiovascular regulation in normotensive and hypotensive rats. Auton Neurosci. 2015;193:63–8. doi: 10.1016/j.autneu.2015.07.009.
    1. Yamawaki H, Takahashi M, Mukohda M, Morita T, Okada M, Hara Y. A novel adipocytokine, nesfatin-1 modulates peripheral arterial contractility and blood pressure in rats. Biochem Biophys Res Commun. 2012;418(4):676–81. doi: 10.1016/j.bbrc.2012.01.076.
    1. Leivo-Korpela S, Lehtimäki L, Hämälainen M, Vuolteenaho K, Kööbi L, Järvenpää R, Kankaanranta H, Saarelainen S, Moilanen E. Adipokines NUCB2/nesfatin-1 and visfatin as novel inflammatory factors in chronic obstructive pulmonary disease. Mediat Inflamm. 2014;2014:232167. doi: 10.1155/2014/232167.
    1. Jiang L, Bao J, Zhou X, Xiong Y, Wu L. Increased serum levels and chondrocyte expression of nesfatin-1 in patients with osteoarthritis and its relation with BMI, hsCRP, and IL-18. Mediat Inflamm. 2013;2013:631251.
    1. Jander S, Sitzer M, Schumann R, Schroeter M, Siebler M, Steinmetz H, Stoll G. Inflammation in high-grade carotid stenosis: a possible role for macrophages and T cells in plaque destabilization. Stroke. 1998;29(8):1625–30. doi: 10.1161/01.STR.29.8.1625.
    1. Tang C-H, Fu X-J, Xu X-L, Wei X-J, Pan H-S. The anti-inflammatory and antiapoptotic effects of nesfatin-1 in the traumatic rat brain. Peptides. 2012;36(1):39–45. doi: 10.1016/j.peptides.2012.04.014.
    1. Kolgazi M, Ozdemir-Kumral ZN, Cantali-Ozturk C, Demirci EK, Yuksel M, Sirvanci S, Yegen BC. Anti-inflammatory effects of nesfatin-1 on acetic acid-induced gastric ulcer in rats: involvement of cyclo-oxygenase pathway. J Physiol Pharmacol. 2017;68(5):765–77.
    1. Sahin FK, Sahin SB, Ural UM, Cure MC, Senturk S, Tekin YB, Balik G, Cure E, Yuce S, Kirbas A. Nesfatin-1 and Vitamin D levels may be associated with systolic and diastolic blood pressure values and hearth rate in polycystic ovary syndrome. Bosnian J Basic Med Sci. 2015;15(3):57–63. doi: 10.17305/bjbms.2015.432.
    1. Zhai T, Li SZ, Fan XT, Tian Z, Lu XQ, Dong J. Circulating nesfatin-1 levels and type 2 diabetes: a systematic review and meta-analysis. J Diabetes Res. 2017 doi: 10.1155/2017/7687098.
    1. Dong J, Xu H, Xu H, et al. Nesfatin-1 stimulates fatty-acid oxidation by activating AMP-activated protein kinase in STZ-induced type 2 diabetic mice. PLoS ONE. 2013;8(12):e83397. doi: 10.1371/journal.pone.0083397.
    1. Yin Y, Li Z, Gao L, Li Y, Zhao J, Zhang W. AMPK-dependent modulation of hepatic lipid metabolism by nesfatin-1. Mol Cell Endocrinol. 2015;417:20–6. doi: 10.1016/j.mce.2015.09.006.
    1. Yang G, Li Y, Cui L, Jiang H, Li X, Jin C, Jin D, Zhao G, Jin J, Sun R, et al. Increased plasma dipeptidyl peptidase-4 activities in patients with coronary artery disease. PLoS ONE. 2016;11(9):e0163027. doi: 10.1371/journal.pone.0163027.
    1. Li JW, Chen YD, Chen WR, You Q, Li B, Zhou H, Zhang Y, Han TW. Prognostic value of plasma DPP4 activity in ST-elevation myocardial infarction. Cardiovasc Diabetol. 2017;16(1):72. doi: 10.1186/s12933-017-0553-3.
    1. Li JW, Chen YD, Chen WR, Jing J, Liu J, Yang YQ. Plasma DPP4 activity is associated with no-reflow and major bleeding events in Chinese PCI-treated STEMI patients. Sci Rep. 2016;6:39412. doi: 10.1038/srep39412.
    1. Aghili N, Devaney JM, Alderman LO, Zukowska Z, Epstein SE, Burnett MS. Polymorphisms in dipeptidyl peptidase IV gene are associated with the risk of myocardial infarction in patients with atherosclerosis. Neuropeptides. 2012;46(6):367–71. doi: 10.1016/j.npep.2012.10.001.
    1. Santamarina M, Carlson CJ. Review of the cardiovascular safety of dipeptidyl peptidase-4 inhibitors and the clinical relevance of the CAROLINA trial. BMC Cardiovasc Disord. 2019;19(1):60. doi: 10.1186/s12872-019-1036-0.
    1. Sauvé M, Ban K, Abdul Momen M, Zhou YQ, Henkelman RM, Husain M, Drucker DJ. Genetic deletion or pharmacological inhibition of dipeptidyl peptidase-4 improves cardiovascular outcomes after myocardial infarction in mice. Diabetes. 2010;59:1063–73. doi: 10.2337/db09-0955.
    1. Connelly K, Zhang Y, Advani A, Advani S, Thai K, Yuen D, Gilbert R. DPP-4 inhibition attenuates cardiac dysfunction and adverse remodeling following myocardial infarction in rats with experimental diabetes. Cardiovasc Ther. 2013;31:259–67. doi: 10.1111/1755-5922.12005.
    1. Kim M, Platt MJ, Shibasaki T, Quaggin SE, Backx PH, Seino S, Simpson JA, Drucker DJ. GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat Med. 2013;19:567–75. doi: 10.1038/nm.3128.
    1. Zheng TP, Liu YH, Yang LX, Qin SH, Liu HB. Increased plasma dipeptidyl peptidase-4 activities are associated with high prevalence of subclinical atherosclerosis in Chinese patients with newly diagnosed type 2 diabetes: a cross-sectional study. Atherosclerosis. 2015;242(2):580–8. doi: 10.1016/j.atherosclerosis.2015.07.042.
    1. Pala L, Mannucci E, Pezzatini A, Ciani S, Sardi J, Raimondi L, et al. Dipeptidyl peptidase-IV expression and activity in human glomerular endothelial cells. Biochem Biophys Res Commun. 2003;310:28–31. doi: 10.1016/j.bbrc.2003.08.111.
    1. Fadini GP, Albiero M, Menegazzo L, de Kreutzenberg SV, Avogaro A. The increased dipeptidyl peptidase-4 activity is not counteracted by optimized glucose control in type 2 diabetes, but is lower in metformin-treated patients. Diabetes Obes Metab. 2012;14:518–22. doi: 10.1111/j.1463-1326.2011.01550.x.

Source: PubMed

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