LAUSR

Background: Myocardial infarction (MI) occurs when blood flow to a region of the myocardium is interrupted. Over time, the damaged myocardium is replaced with scar tissue through activation of an inflammatory phase, followed by a reparative and a maturation phase. A disintegrin and metalloproteinase-15 (ADAM15) is a membrane-bound enzyme that is expressed in inflammatory cells and the heart, and its expression in the heart is increased following myocardial infarction. However, its function in heart disease has not yet been explored. We hypothesized that ADAM15 deficiency will impede the inflammatory response post-MI, which could reduce inflammation but also hinder scar formation causing adverse remodeling of the surviving myocardium. Methods: MI was induced in adult male wildtype (WT) and ADAM15-deficient ( Adam15 -/- ) mice by permanent ligation of the left anterior descending artery. LV structure, systolic and diastolic functions were assessed by echocardiography. Hearts were excised at 3-days or 1 week post-MI, processed for histological and molecular analyses. Fibrillar collagen organization was assessed by Second Harmonic Generation. Cardiac fibroblasts (cFBs) were isolated from WT or Adam15 -/- hearts, and subjected to ischemia (hypoxia + nutrient deletion) in vitro . Results: Adam15 -/- mice exhibited significantly compromised survival post-MI, mainly due to LV rupture. Cardiac contractility was reduced in Adam15 -/- compared to WT-MI mice. Collagen fibers in the scar tissue were distorted and scarce in Adam15 -/- MI hearts, associated with reduced levels of a major cross-linking enzyme, lysyl oxidase. In vitro, Adam15 -/- cFBs showed impaired myofibroblast transformation under ischemic conditions, suggesting attenuated fibroblast activation. Conclusion: Adam15 -deficiency impairs the wound healing process post-MI, leading to deleterious remodelling and LV rupture.