Background and Purpose. Remodeling of the extracellular matrix (ECM) is a key event after myocardial infarction (MI) which critically impacts on heart failure progression. ECM remodeling is characterized by activation of myofibroblasts via alpha-smooth muscle actin (α-SMA). Pharmacological inhibition of the metalloprotease ADAM10 as well as cardiomyocyte specific ADAM10 knock out improve cardiac function and survival after infarction and reduce scar size. Here, we investigate the role of ADAM10 in ECM remodeling after myocardial infarction and analyze its impact on cardiomyocyte function.

Methods and results. ECM remodeling was assessed in sham-operated, DMSO and ADAM10-inhibitor (GI254023X) treated mice 28 days after permanent ligation of the left anterior descending artery (LAD). The infarct matrisome was determined using mass spectrometry of decellularized and ECM-enriched mouse hearts. MS analysis revealed upregulation ECM proteins such as Collagen I, Collagen VI, Fibronectin, Periostin and EMILIN-1 after MI (DMSO), which were significantly reduced after ADAM10 inhibition. Cultivation of primary ventricular mouse cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes (iCMs) on these matrices resulted in compromised cell shape, significantly increased beating rates and contraction velocities. Hypoxia/reoxygenation experiments with iCMs and human ventricular fibroblasts (HVF) identified an ADAM10-dependend cardiomyocyte-fibroblast crosstalk to induce α-SMA levels in HVF and control extracellular ECM protein deposition. Secretome analysis of CRISOR/Cas9-induced ADAM10 knockout iCMs will identify the underlying mechanisms.

Conclusion. Here we show that inhibition of ADAM10 after MI significantly reduces a maladaptive ECM remodeling to reduce post-MI scaring. Moreover, cardiomyocyte-specific ADAM10 regulates the secretion of ECM proteins by ventricular fibroblasts. Thus, ADAM10 might be a nodal protein for cardiomyocyte-fibroblast communication after infarction.