Angiotensin Converting Enzyme Inhibitors (ACEIs) Decrease the Progression of Cardiac Fibrosis in Rheumatic Heart Disease Through the Inhibition of IL-33/sST2

Ade M Ambari, Budhi Setianto, Anwar Santoso, Basuni Radi, Bambang Dwiputra, Eliana Susilowati, Fadilla Tulrahmi, Pieter A Doevendans, Maarten J Cramer, Ade M Ambari, Budhi Setianto, Anwar Santoso, Basuni Radi, Bambang Dwiputra, Eliana Susilowati, Fadilla Tulrahmi, Pieter A Doevendans, Maarten J Cramer

Abstract

Rheumatic heart disease (RHD) is common in developing countries and poses a big medical challenge and burden. The pathogenesis of RHD is influenced by the triad of host, agent, and environment. Autoantigens generated from Group A Streptococcus (GAS) infection are captured by the resident dendritic cells (DCs) in the heart's valvular endothelium. DCs differentiate into antigen presenting cells (APC) in the valve interstices. APC induces activation of autoreactive T cells, which triggers inflammation and tissue fibrosis. Cardiac fibrosis is promoted through the activation of Mitogen activated protein kinases (MAPKs) and its downstream signaling, including its interaction with transforming growth factor-β (TGF-β) and Smad proteins. TGF-β-induced phosphorylation of Smad2 complexes with Smad3 and Smad4, and translocates into the nucleus. Angiotensin II enhances the migration, maturation, and presentation of DC. In RHD, Angiotensin II induces fibrosis via the stimulation of TGF-β, which further increases the binding of IL-33 to sST2 but not ST2L, resulting in the upregulation of Angiotensin II and progression of cardiac fibrosis. This cascade of inflammation and valvular fibrosis causes calcification and stiffening of the heart valves in RHD. Angiotensin converting enzyme inhibitors (ACEIs) inhibit Angiotensin II production, which in turn decreases TGF-β expression and the onset of overt inflammatory response. This condition leads to a reduction in the sST2 as the decoy receptor to "steal" IL-33, and IL-33 binds to ST2L and results in cardioprotection against cardiac fibrosis in the pathogenesis of RHD.

Keywords: IL-33; ST2; angiotensin converting enzyme; cardiac fibrosis; cardiac fibrosis and angiotensin converting enzyme inhibitors; rheumatic heart disease.

Copyright © 2020 Ambari, Setianto, Santoso, Radi, Dwiputra, Susilowati, Tulrahmi, Doevendans and Cramer.

Figures

Figure 1
Figure 1
Hypothesis.
Figure 2
Figure 2
Immune response to GAS.
Figure 3
Figure 3
ACE-I and ST2 involvement in cardiac fibrosis of RHD.

References

    1. Watkins DA, Beaton AZ, Carapetis JR, Karthikeyan G, Mayosi BM, Wyber R, et al. . Rheumatic heart disease worldwide: JACC scientific expert panel. J Am Coll Cardiol. (2018) 72:1397–416. 10.1016/j.jacc.2018.06.063
    1. Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal diseases. Lancet Infect Dis. (2005) 5:685–94. 10.1016/S1473-3099(05)70267-X
    1. World Health Organization - WHO Health Statistics and Information Systems|Disease Burden and Mortality Estimates. World Heal Organ. (2018). p. 3–5. Available online at:
    1. Mayosi B, Robertson K, Volmink J, Adebo W, Akinyore K, Amoah A, et al. . The Drakensberg declaration on the control of rheumatic fever and rheumatic heart disease in Africa. S Afr Med J. (2006) 96:246.
    1. Carapetis JR, Wolff DR, Currie BJ. Acute rheumatic fever and rheumatic heart disease in the top end of Australia's Northern Territory. Med J Aust. (1996) 164:146–9.
    1. Guilherme L, Kalil J. Rheumatic fever and rheumatic heart disease: cellular mechanisms leading autoimmune reactivity and disease. J Clin Immunol. (2010) 30:17–23. 10.1007/s10875-009-9332-6
    1. Travers JG, Kamal FA, Robbins J, Yutzey KE, Blaxall BC. Cardiac fibrosis: the fibroblast awakens. Circ Res. (2016) 118:1021–40. 10.1161/CIRCRESAHA.115.306565
    1. Murphy AM, Wong AL, Bezuhly M. Modulation of angiotensin II signaling in the prevention of fibrosis. Fibrogenesis Tissue Repair. (2015) 8:7. 10.1186/s13069-015-0023-z
    1. Habashi JP, Doyle JJ, Holm TM, Aziz H, Schoenhoff F, Bedja D, et al. . Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism. Science. (2011) 332:361–5. 10.1126/science.1192152
    1. Anand IS, Rector TS, Kuskowski M, Snider J, Cohn JN. Prognostic value of soluble ST2 in the valsartan heart failure trial. Circ Heart Fail. (2014) 7:418–26. 10.1161/CIRCHEARTFAILURE.113.001036
    1. Chen Q, Carroll HP, Gadina M. The newest interleukins: recent additions to the ever-growing cytokine family. Vitam Horm. (2006) 74:207–28. 10.1016/S0083-6729(06)74008-0
    1. Ferrario CM. Cardiac remodelling and RAS inhibition. Ther Adv Cardiovasc Dis. (2016) 10:162–71. 10.1177/1753944716642677
    1. Fieber C, Kovarik P. Responses of innate immune cells to group A Streptococcus. Front Cell Infect Microbiol. (2014) 4:140. 10.3389/fcimb.2014.00140
    1. Soderholm AT, Barnett TC, Sweet MJ, Walker MJ. Group A streptococcal pharyngitis: Immune responses involved in bacterial clearance and GAS-associated immunopathologies. J Leukoc Biol. (2018) 103:193–213. 10.1189/jlb.4MR0617-227RR
    1. Döhrmann S, Cole JN, Nizet V. Conquering neutrophils. PLoS Pathog. (2016) 12:e1005682. 10.1371/journal.ppat.1005682
    1. Bozinovski S, Seow HJ, Chan SPJ, Anthony D, McQualter J, Hansen M, et al. . Innate cellular sources of interleukin-17A regulate macrophage accumulation in cigarette- smoke-induced lung inflammation in mice. Clin Sci. (2015) 129:785–96. 10.1042/CS20140703
    1. Chen X, Li N, Bi S, Wang X, Wang B. Co-Activation of Th17 and antibody responses provides efficient protection against mucosal infection by group a streptococcus. PLoS ONE. (2016) 11:e0168861. 10.1371/journal.pone.0168861
    1. Fieber C, Janos M, Koestler T, Gratz N, Li X-D, Castiglia V, et al. . Innate immune response to streptococcus pyogenes depends on the combined activation of TLR13 and TLR2. PLoS ONE. (2015) 10:e0119727. 10.1371/journal.pone.0119727
    1. Dinis M, Plainvert C, Kovarik P, Longo M, Fouet A, Poyart C. The innate immune response elicited by Group A Streptococcus is highly variable among clinical isolates and correlates with the emm type. PLoS ONE. (2014) 9:e101464. 10.1371/journal.pone.0101464
    1. Mishalian I, Ordan M, Peled A, Maly A, Eichenbaum MB, Ravins M, et al. . Recruited macrophages control dissemination of group A Streptococcus from infected soft tissues. J Immunol. (2011) 187:6022–31. 10.4049/jimmunol.1101385
    1. Castiglia V, Piersigilli A, Ebner F, Stoiber D, Lienenklaus S, Weiss S, et al. Type I Interferon signaling prevents IL-1 b -driven lethal systemic hyperinflammation during invasive bacterial infection of soft tissue article type i interferon signaling prevents IL-1 b -driven lethal systemic hyperinflammation during invasive bacterial infection of soft tissue. (2016) 19:375–87. 10.1016/j.chom.2016.02.003
    1. Joosten LAB, Koenders MI, Smeets RL, Heuvelmans-Jacobs M, Helsen MMA, Takeda K, et al. . Toll-like receptor 2 pathway drives streptococcal cell wall-induced joint inflammation: critical role of myeloid differentiation factor 88. J Immunol. (2003) 171:6145–53. 10.4049/jimmunol.171.11.6145
    1. Loof TG, Goldmann O, Medina E. Immune recognition of Streptococcus pyogenes by dendritic cells. Infect Immun. (2008) 76:2785–92. 10.1128/IAI.01680-07
    1. Goldmann O, Lengeling A, Böse J, Geffers R, Chhatwal GS, Goldmann O, et al. . The role of the MHC on resistance to group a streptococci in mice 1. (2020) 175:3862–72. 10.4049/jimmunol.175.6.3862
    1. Tsatsaronis JA, Walker MJ, Sanderson-smith ML. Host responses to group a streptococcus : cell death and inflammation. (2014) 10:1–7. 10.1371/journal.ppat.1004266
    1. Veckman V, Miettinen M, Pirhonen J, Sirén J, Matikainen S, Julkunen I. Streptococcus pyogenes and Lactobacillus rhamnosus differentially induce maturation and production of Th1-type cytokines and chemokines in human monocyte-derived dendritic cells. J Leukoc Biol. (2004) 75:764–71. 10.1189/jlb.1003461
    1. Dong C. IL-23/IL-17 biology and therapeutic considerations. J Immunotoxicol. (2008) 5:43–6. 10.1080/15476910801897953
    1. Moser M, Leo O. Key concepts in immunology. Vaccine. (2010) 28:C2–C13. 10.1016/j.vaccine.2010.07.022
    1. Guilherme L, Köhler KF, Postol E, Kalil J. Genes, autoimmunity and pathogenesis of rheumatic heart disease. Ann Pediatr Cardiol. (2011) 4:13–21. 10.4103/0974-2069.79617
    1. Roberts S, Kosanke S, S TD, Jankelow D, Duran CM, Cunningham MW. Pathogenic mechanisms in rheumatic carditis: focus on valvular endothelium. J Infect Dis. (2001) 183:507–11. 10.1086/318076
    1. Bryant PA, Robins-Browne R, Carapetis JR, Curtis N. Some of the people, some of the time: susceptibility to acute rheumatic fever. Circulation. (2009) 119:742–53. 10.1161/CIRCULATIONAHA.108.792135
    1. Parks T, Mirabel MM, Kado J, Auckland K, Nowak J, Rautanen A, et al. . Association between a common immunoglobulin heavy chain allele and rheumatic heart disease risk in Oceania. Nat Commun. (2017) 8:14946. 10.1038/ncomms14946
    1. Cunningham MW. Rheumatic fever, autoimmunity, and molecular mimicry: the streptococcal connection. Int Rev Immunol. (2014) 33:314–29. 10.3109/08830185.2014.917411
    1. Galvin JE, Hemric ME, Ward K, Cunningham MW. Cytotoxic mAb from rheumatic carditis recognizes heart valves and laminin. J Clin Invest. (2000) 106:217–24. 10.1172/JCI7132
    1. Kirvan CA, Swedo SE, Heuser JS, Cunningham MW. Mimicry and autoantibody-mediated neuronal cell signaling in Sydenham chorea. Nat Med. (2003) 9:914–20. 10.1038/nm892
    1. Kneass ZT, Marchase RB. Protein O-GlcNAc modulates motility-associated signaling intermediates in neutrophils. J Biol Chem. (2005) 280:14579–85. 10.1074/jbc.M414066200
    1. Sanada S, Hakuno D, Higgins L, R Schreiter E, N.J., McKenzie A, T Lee R. IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system. J Clin Invest. (2007) 117:1538–49. 10.1172/JCI30634
    1. Miller AM. Role of IL-33 in inflammation and disease. J Inflamm (Lond). (2011) 8:22. 10.1186/1476-9255-8-22
    1. Tandon R, Sharma M, Chandrashekhar Y, Kotb M, Yacoub MH, Narula J. Revisiting the pathogenesis of rheumatic fever and carditis. Nat Rev Cardiol. (2013) 10:171–7. 10.1038/nrcardio.2012.197
    1. Kupfahl C, Pink D, Friedrich K, Zurbrügg HR, Neuss M, Warnecke C, et al. . Angiotensin II directly increases transforming growth factor beta1 and osteopontin and indirectly affects collagen mRNA expression in the human heart. Cardiovasc Res. (2000) 46:463–75. 10.1016/s0008-6363(00)00037-7
    1. Schultz JEJ, Witt SA, Glascock BJ, Nieman ML, Reiser PJ, Nix SL, et al. . TGF-beta1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II. J Clin Invest. (2002) 109:787–96. 10.1172/JCI14190
    1. Braicu C, Buse M, Busuioc C, Drula R, Gulei D, Raduly L, et al. . A comprehensive review on MAPK: a promising therapeutic target in cancer. Cancers. (2019) 11:1618. 10.3390/cancers11101618
    1. Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. (2011) 75:50–83. 10.1128/MMBR.00031-10
    1. Kehat I. Extracellular signal-regulated kinases 1 / 2 as regulators of cardiac hypertrophy. (2015) 6:1–8. 10.3389/fphar.2015.00149
    1. Mebratu Y, Tesfaigzi Y. How ERK1/2 activation controls cell proliferation and cell death: Is subcellular localization the answer? Cell Cycle. (2009) 8:1168–75. 10.4161/cc.8.8.8147
    1. Roskoski RJ. ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res. (2012) 66:105–43. 10.1016/j.phrs.2012.04.005
    1. Gureasko J, Galush WJ, Boykevisch S, Sondermann H, Bar-Sagi D, Groves JT, et al. . Membrane-dependent signal integration by the Ras activator Son of sevenless. Nat Struct Mol Biol. (2008) 15:452–61. 10.1038/nsmb.1418
    1. McKay MM, Morrison DK. Integrating signals from RTKs to ERK/MAPK. Oncogene. (2007) 26:3113–21. 10.1038/sj.onc.1210394
    1. Bogoyevitch MA, Ngoei KRW, Zhao TT, Yeap YYC, Ng DCH. c-Jun N-terminal kinase (JNK) signaling: recent advances and challenges. Biochim Biophys Acta. (2010) 1804:463–75. 10.1016/j.bbapap.2009.11.002
    1. Shi J-H, Sun S-C. Tumor necrosis factor receptor-associated factor regulation of nuclear factor κB and mitogen-activated protein kinase pathways. Front Immunol. (2018) 9:1849. 10.3389/fimmu.2018.01849
    1. Gui T, Sun Y, Shimokado A, Muragaki Y. The roles of mitogen-activated protein kinase pathways in TGF-β-induced epithelial-mesenchymal transition. J Signal Transduct. (2012) 2012:289243. 10.1155/2012/289243
    1. Meng X-M, Nikolic-Paterson DJ, Lan HY. TGF-β: the master regulator of fibrosis. Nat Rev Nephrol. (2016) 12:325–38. 10.1038/nrneph.2016.48
    1. Walton KL, Johnson KE, Harrison CA. Targeting TGF-β mediated SMAD signaling for the prevention of fibrosis. Front Pharmacol. (2017) 8:461. 10.3389/fphar.2017.00461
    1. Shi Y, Massague J. Mechanisms of TGF-? signaling from cell membrane to the nucleus. (2003) 113:685–700. 10.1016/s0092-8674(03)00432-x
    1. Dulin NO, Ard S, Reed E, Smolyaninova L, Orlov SN, Guzy R, Mutlu GM. Sustained SMAD2 phosphorylation is required for myofibroblast transformation in response to TGF-beta. In: C62. FIBROBLAST BIOLOGY American Thoracic Society International Conference Abstracts. (American Thoracic Society; ) (2019). p. A5350–A5350. 10.1164/ajrccm-conference.2019.199.1_MeetingAbstracts.A5350
    1. Yao F, He Z, Lu M, Li P, Wang J. Smad2 and Smad3 play differential roles in the regulation of matrix deposition-related enzymes in renal mesangial cells. Int J Clin Exp Med. (2017) 10:10161–9.
    1. Ali NA, McKay MJ, Molloy MP. Proteomics of Smad4 regulated transforming growth factor-beta signalling in colon cancer cells. Mol Biosyst. (2010) 6:2332–8. 10.1039/C0MB00016G
    1. Luo K. Signaling Cross Talk between TGF-β/Smad. Cold Spring Harb Perspect Biol. (2017) 9:a022137. 10.1101/cshperspect.a022137
    1. Kakkar R, Lee RT. The IL-33/ST2 pathway: therapeutic target and novel biomarker. Nat Rev Drug Discov. (2008) 7:827–40. 10.1038/nrd2660
    1. Marzullo A, Ambrosi F, Inchingolo M, Manca F, Devito F, Angiletta D, et al. . ST2L transmembrane receptor expression: an immunochemical study on endarterectomy samples. PLoS ONE. (2016) 11:1–12. 10.1371/journal.pone.0156315
    1. L Januzzi J. ST2 as a cardiovascular risk biomarker: from the bench to the bedside. J Cardiovasc Transl Res. (2013) 6:493–500. 10.1007/s12265-013-9459-y
    1. Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. (2005) 23:479–90. 10.1016/j.immuni.2005.09.015
    1. Caporali A, Meloni M, Miller AM, Vierlinger K, Cardinali A, Spinetti G, et al. . Soluble ST2 is regulated by p75 neurotrophin receptor and predicts mortality in diabetic patients with critical limb ischemia. Arterioscler Thromb Vasc Biol. (2012) 32:e149–e160. 10.1161/ATVBAHA.112.300497
    1. Li D, Guabiraba R, Besnard A-G, Komai-Koma M, Jabir MS, Zhang L, et al. . IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice. J Allergy Clin Immunol. (2014) 134:1422–32.e11. 10.1016/j.jaci.2014.05.011
    1. Ramona J, von M, Martin F, Luchner A. Soluble ST2 - a potential biomarker of rheumatic heart disease. Clin Med Rev Case Rep. (2019) 6:1–4. 10.23937/2378-3656/1410255
    1. Howell EJ, Butcher JT. Valvular heart diseases in the developing world: developmental biology takes center stage. J Heart Valve Dis. (2012) 21:234–40.
    1. Li Y, Ni S, Meng Y, Shi X, Zhao X, Luo H, et al. . Angiotensin II facilitates fibrogenic effect of TGF- b 1 through enhancing the down-regulation of BAMBI caused by LPS : a new pro-fibrotic mechanism of angiotensin II. PLoS ONE. (2013) 8:e76289. 10.1371/journal.pone.0076289
    1. Wang L, Li Y-L, Zhang C-C, Cui W, Wang X, Xia Y, et al. . Inhibition of Toll-Like receptor 2 reduces cardiac fibrosis by attenuating macrophage-mediated inflammation. Cardiovasc Res. (2013) 101:383–392. 10.1093/cvr/cvt258
    1. Zhang YE. Non-smad pathways in TGF-beta signaling. Cell Res. (2009) 19:128–39. 10.1038/cr.2008.328
    1. Ehanire T, Ren L, Bond J, Medina M, Li G, Bashirov L, et al. Angiotensin II stimulates canonical TGF-β signaling pathway through angiotensin type 1 receptor to induce granulation tissue contraction. J Mol Med (Berl). (2015) 93:289–302. 10.1007/s00109-014-1211-9
    1. Crowley SD, Rudemiller NP. Immunologic effects of the renin-angiotensin system. JASN (2017) 28:1350–61. 10.1681/ASN.2016101066
    1. Su JB. Different cross-talk sites between the renin – angiotensin and the kallikrein – kinin systems. Angiotensin Aldosterone Syst. (2014) 15:319–28. 10.1177/1470320312474854
    1. Hus-Citharel A, Bouby N, Iturrioz X, Llorens-Cortes C. Multiple cross talk between angiotensin II, bradykinin, and insulin signaling in the cortical thick ascending limb of rat kidney. Endocrinology. (2010) 151:3181–94. 10.1210/en.2009-1237
    1. Abareshi A, Norouzi F, Asgharzadeh F, Beheshti F, Hosseini M, Farzadnia M, et al. . Effect of angiotensin-converting enzyme inhibitor on cardiac fibrosis and oxidative stress status in lipopolysaccharide-induced inflammation model in rats. Int J Prev Med. (2017) 8:69. 10.4103/ijpvm.IJPVM_322_16
    1. De Albuquerque DA, Saxena V, Adams DE, Boivin GP, Brunner HI, Witte DP, et al. . An ACE inhibitor reduces Th2 cytokines and TGF-beta1 and TGF-beta2 isoforms in murine lupus nephritis. Kidney Int. (2004) 65:846–59. 10.1111/j.1523-1755.2004.00462.x
    1. Perez O, Garvin A, Hale T. Transient ACE-inhibitor treatment produces persistent change in cardiac fibroblast physiology. FASEB J. (2018) 32:867.4. 10.1096/fasebj.2018.32.1_supplement.867.4
    1. Maskito VJ, Anniwati L. The difference between st2 and nt-pro bnp concentrations before and after-treatment of ace-inhibitors in nyha iii-iv heart failure patients. Indones J Clin Pathol Med Lab. (2019) 26:11–17. 10.24293/ijcpml.v26i1.1366
    1. Tan W-Q, Fang Q-Q, Shen XZ, Giani JF, Zhao T V, Shi P, et al. . Angiotensin-converting enzyme inhibitor works as a scar formation inhibitor by down-regulating Smad and TGF-β-activated kinase 1 (TAK1) pathways in mice. Br J Pharmacol. (2018) 175:4239–52. 10.1111/bph.14489
    1. Platten M, Youssef S, Hur EM, Ho PP, Han MH, Lanz T V, et al. . Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1- and TH17-mediated autoimmunity. Proc Natl Acad Sci USA. (2009) 106:14948–53. 10.1073/pnas.0903958106
    1. Dai Q, Xu M, Yao M, Sun B. Angiotensin AT1 receptor antagonists exert anti-inflammatory effects in spontaneously hypertensive rats. Br J Pharmacol. (2008) 152:1042–8. 10.1038/sj.bjp.0707454
    1. Lapteva N, Ide K, Nieda M, Ando Y, Hatta-Ohashi Y, Minami M, et al. . Activation and suppression of renin-angiotensin system in human dendritic cells. Biochem Biophys Res Commun. (2002) 296:194–200. 10.1016/s0006-291x(02)00855-0
    1. Muller DN, Shagdarsuren E, Park J-K, Dechend R, Mervaala E, Hampich F, et al. . Immunosuppressive treatment protects against angiotensin II-induced renal damage. Am J Pathol. (2002) 161:1679–93. 10.1016/S0002-9440(10)64445-8
    1. Nahmod KA, Vermeulen ME, Raiden S, Salamone G, Gamberale R, Fernández-Calotti P, et al. . Control of dendritic cell differentiation by angiotensin II. FASEB J. (2003) 17:491–3. 10.1096/fj.02-0755fje
    1. Griesenauer B, Paczesny S. The ST2/IL-33 axis in immune cells during inflammatory diseases. Front Immunol. (2017) 8:475. 10.3389/fimmu.2017.00475

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir