Background and Purpose. Deposition of extracellular matrix (ECM) proteins and scar formation are essential to keep the structural integrity of the heart after myocardial infarction. Excessive ECM remodeling, however, tremendously impacts on post-infarction cardiac function. Pharmacological inhibition of the metalloprotease ADAM10 and cardiomyocyte-specific ADAM10 knockout 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). Mass spectrometry (MS) of decellularized and ECM-enriched mouse hearts revealed upregulation ECM proteins such as collagen I, collagen VI, fibronectin, periostin and emilin-1 in infarcted hearts (DMSO), which were significantly reduced after ADAM10 inhibition. MS results were validated by quantitative real-time PCR, light sheet microscopy and immunofluorescence staining of extracellular collagen I and fibronectin. Hypoxia/reoxygenation experiments identified an ADAM10-dependend cardiomyocyte-fibroblast crosstalk to control ECM protein expression. In-depth evaluation of the differentially regulated ECM proteins revealed impairment of cardiomyocyte contraction and structure.

Conclusion. Here, we show that inhibition of ADAM10 after myocardial infarction significantly reduces maladaptive upregulation of ECM proteins, thereby reducing post-myocardial infarction scarring. Moreover, cardiomyocyte-specific ADAM10 regulates the secretion of ECM proteins by ventricular fibroblasts. Thus, we identify ADAM10 as a potential nodal protein for intercellular communication after infarction.