Background and Aim.
Despite advances in myocardial infarction (MI) therapy, many patients develop heart failure due to adverse remodeling, emphasizing the need for novel molecular targets. Members of the A disintegrin and metalloproteinase (ADAM) family have emerged as important regulators of inflammation, fibrosis, and angiogenesis, making them promising candidates in cardiovascular research. While early inhibition of ADAM10 after MI improves cardiac outcome through immune modulation, the role of ADAM9 in post-infarction remodeling remains largely unexplored. This study aimed to investigate the impact of pharmacological inhibition and genetic deletion of ADAM9 on cardiac function, remodeling, and underlying molecular mechanisms after MI.
Methods and Results.
We combined analyses in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), human umbilical vein endothelial cells (HUVECs), human heart tissue biopsies, and murine models employing both a peptide-based ADAM9 inhibition (A9i) and genetic knockout (KO) mice. ADAM9 expression (mRNA and protein) was markedly upregulated in failing human hearts and in murine hearts post-MI, especially within the infarct zone. A9i treatment significantly improved cardiac function after MI, accompanied by a substantial reduction in fibrotic area and scar size. Comparable cardioprotective effects were observed in ADAM9 KO mice. Transcriptomic and proteomic analyses (RNA sequencing, Western Blotting, immunohistochemistry, flow cytometry) revealed that these functional and structural benefits were associated with downregulation of angiotensin-converting enzyme (ACE) expression through reduced HB-EGF shedding and modulation of EGFR/ERK1/2 signaling. Although expressed in both cardiomyocytes and endothelial cells, functional studies identified endothelial ADAM9 as mediator of adverse cardiac remodeling. Notably, systemic ACE activity, blood pressure and other RAAS-related organ functions remained unchanged following A9i treatment, indicating a localized, heart-specific mode of action.
Conclusion and Clinical Impact.
Targeting ADAM9 preserves cardiac function, reduces fibrosis and scar formation after MI through endothelial-specific modulation of the HB-EGF/EGFR/ERK/ACE axis. By selectively attenuating pathological RAAS activation in cardiac tissue without systemic side effects, ADAM9 represents a promising therapeutic approach for infarct patients in whom conventional RAAS blockade is limited by impairment, renal dysfunction, or electrolyte disturbances.
