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

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.

Immediate Renal Denervation After Acute Myocardial Infarction Mitigates the Progression of Heart Failure via the Modulation of IL-33/ST2 Signaling

“…Second, in this study we discovered for the first time that RDN protected the failing heart via the modulation of IL-33/ST2 signaling, yet the detailed mechanism is still unclear. Existing studies have found that changes in IL-33/ST2 pathway are associated with the RAAS system (43,44). Since RAAS is regulated by RDN, we speculate that RDN may exert a cardioprotective effect on IL-33/ST2 pathway through RAAS and further detailed mechanisms are under exploration.…”

Roles of IL-33 in the Pathogenesis of Cardiac Disorders

“…Angiotensin II was shown to promote IL-33 and ST2L expression by stimulating transforming growth factor (TGF)-β to induce fibrosis in RHD while angiotensin-converting enzyme inhibitor inhibited the production of angiotensin II, which in turn promoted the binding of IL-33 to ST2L and alleviated cardiac fibrosis. 70 Thus, IL-33 and ST2L might play a protective role in RHD. In patients with ADHF, elevated sST2 correlates directly with ADHF severity, and powerfully and independently predicts an increased risk of heart failure complications including arrhythmia, pump failure, and death.…”

Novel Therapies for the Treatment of Cardiac Fibrosis Following Myocardial Infarction

“…The inhibition of angiotensin II by angiotensin converting enzyme inhibitors reduces the inflammatory response and the level of sST2. In the absence of sST2, IL-33 interacts with ST2L [ 109 ]. Moreover, in vitro studies have shown that angiotensin II treatment significantly elevated the level of circHIPK3 in the cardiac fibroblasts and surrounding heart tissue.…”