ADAM10 inhibition improves survival and augments cardiac function after myocardial infarction. (25th November 2020)

• Record Type: Journal Article
• Authors: Klapproth, E; Kuenzel, S; Guenscht, M; Lorenz, K; Weber, S; Guan, K; El-Armouche, A
• Is Part Of: European heart journal. Volume 41:(2020)Supplement 2
• Publication Date: 2020-11-25
• Subjects: Ischemia, Infarction, Cardioprotection; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/ehjci/ehaa946.3640
• Languages: English
• ISSNs: 0195-668X

Abstract

Abstract: Background and purpose: Following myocardial infarction (MI), adverse fibrotic remodeling with extensive deposition of extracellular matrix (ECM) components has substantial consequences for the contractility of the ventricle finally leading to terminal heart failure (HF). Recently, inhibition of ECM-remodeling enzymes is discussed as potential treatment option for HF, especially following MI. The metalloprotease ADAM10 plays a crucial role in the development of the cardiovascular system and HF patients show elevated serum levels of the ADAM10 substrates CXCL16 and FasL. However, the causal role of ADAM10 in cardiovascular diseases has not been investigated. Here we evaluate the so far unknown role of ADAM10 in heart failure and after MI. Methods and results: Our study capitalized from human atrial tissue biopsies, a cardiomyocyte-specific ADAM10 knockout (ADAM10 KO) mouse model as well as pharmacological ADAM10 inhibition following MI. ADAM10 expression analysis revealed elevated protein levels in HF patients compared to non-failing hearts. Upon MI, ADAM10 KO and pharmacological ADAM10 inhibition (GI254023X) significantly improved overall survival, significantly enhanced cardiac function (fractional area shortening - FAS, ejection fraction - EF) and significantly reduced infarct sizes. Compared to the high potential angiotensin receptor neprilysin inhibitor (ARNi) LCZ696, ADAM10 inhibition and combined ADAM10i/LCZ696 treatment resulted in preservation of cardiac function that was superior to sole LCZ696 treatment. Mechanistically, this functional improvement was due to reduced shedding of the ADAM10 substrate Notch1, induction of angiogenesis and an ADAM10-dependend inactivation of the NLRP3 inflammasome Conclusion: Our data suggest that ADAM10 targeting is highly efficient for improving post-infarction cardiac function. Due to its overexpression in heart tissue of HF patients, ADAM10 could be a potential molecular target to improve therapy after MI. In terms of overall survival and pathophysiological remodeling following MI, our data suggest a greater potential of the ADAM10i/LCZ696 combinatorial therapy than sole LCZ696 treatment. Funding Acknowledgement: Type of funding source: Public grant(s) – National budget only. Main funding source(s): German Heart Foundation/ German Foundation of Heart Research