Background and Purpose. The metalloprotease ADAM10 plays a crucial role in the development of the cardiovascular system and altered expression levels in response to specific heart pathologies such as cardiomyopathies and atrial fibrillation have been reported. Additionally, heart failure (HF) patients show elevated serum levels of the ADAM10 substrates CXCL16 and FasL. The causal role of ADAM10 in cardiovascular diseases, however, has not been investigated yet. Here we focused on the role of ADAM10 in HF after myocardial infarction (MI).

Methods and Results. Our study uses human tissue biopsies, a cardiomyocyte-specific ADAM10 knockout mouse model (ADAM10 KO) and pharmacological ADAM10 inhibitors. We show that ADAM10 protein levels are elevated HF patients compared to non-failing hearts (2-fold) and ADAM10 mRNA expression correlates with expression of atrial (ANP) and brain natriuretic peptide (BNP) mRNA. Cardiomyocyte-specific ADAM10 KO mice show normal survival and normal cardiac function. However, upon MI via LAD ligation ADAM10 KO and pharmacological ADAM10 inhibition (GI254023X) significantly improved overall survival and preserved cardiac function (fractional area shortening - FAS, ejection fraction - EF). Additionally, ADAM10 inhibited mice showed significantly reduced infarct sizes. Notably, ADAM10 inhibition was superior to treatment with the clinically used angiotensin receptor neprilysin inhibitor LCZ696, used here as appositive control (Figure 1a). Mechanistically, this functional improvement was due to ADAM10-dependend reduction of apoptotic cardiomyocytes, inactivation of the NLRP3 inflammasome (Figure 1b-c) and reduced structural remodeling as evident by lower expression of ECM proteins.

Conclusion. Our data suggest that targeting ADAM10 is highly efficient for improving post-infarction cardiac function and survival. Due to its overexpression in heart tissue of HF patients, ADAM10 could be a potential molecular target to be blocked after MI induced heart failure.