Background and Purpose. Myocardial infarction (MI) represents a major public health burden and post-infarction pharmacotherapy still needs to be improved. Remodeling of the extracellular matrix (ECM) is a key event after MI which is characterized by activation of myofibroblasts via alpha-smooth muscle actin (alpha-SMA). Moreover, post-MI restructuring of ECM proteins has a tremendous impact on heart function. Pharmacological inhibition of the metalloprotease ADAM10 as well as cardiomyocyte specific ADAM10 knock out augments post-infarction cardiac function and survival. To evaluate whether ADAM10 inhibition impacts on cardiac remodeling for improved cardiac function, we here focus on the role of ADAM10 in ECM remodeling and myofibroblast activation after MI.

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 15 upregulated ECM proteins such as collagen I, collagen III, fibronectin and periostin in MI hearts (DMSO) as compared to sham hearts, 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. Additionally, human ventricular fibroblast showed reduced alpha-SMA levels when treated with supernatants from hypoxic GI254023X-treated iPSC-derived cardiomyocytes as compared to DMSO-treated controls. Interestingly, direct ADAM10-inhibition in HVF following hypoxia did not impact on myofibroblast activation.

Conclusion. Here we show that inhibition of ADAM10 after MI significantly reduces a maladaptive upregulation of ECM proteins which reduces post-MI scaring. Additionally, cardiomyocyte-specific ADAM10 regulates ECM protein secretion and alpha-SMA levels in primary human fibroblasts. As such, we identify ADAM10 as a potentially nodal protein for post-infarction intercellular communication. Due to its overexpression in heart tissue of HF patients, ADAM10 could be a potential molecular target after MI.