Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction

Matrix metalloproteinase-9 (MMP-9) is prominently overexpressed after myocardial infarction (MI). We tested the hypothesis that mice with targeted deletion of MMP9 have less left ventricular (LV) dilation after experimental MI than do sibling wild-type (WT) mice. Animals that survived ligation of the left coronary artery underwent echocardiographic studies after MI; all analyses were performed without knowledge of mouse genotype. By day 8, MMP9 knockout (KO) mice had significantly smaller increases in end-diastolic and end-systolic ventricular dimensions at both midpapillary and apical levels, compared with infarcted WT mice; these differences persisted at 15 days after MI. MMP-9 KO mice had less collagen accumulation in the infarcted area than did WT mice, and they showed enhanced expression of MMP-2, MMP-13, and TIMP-1 and a reduced number of macrophages. We conclude that targeted deletion of the MMP9 gene attenuates LV dilation after experimental MI in mice. The decrease in collagen accumulation and the enhanced expression of other MMPs suggest that MMP-9 plays a prominent role in extracellular matrix remodeling after MI

Endothelial to Mesenchymal Transition in Cardiovascular Disease: Key Mechanisms and Clinical Translation Opportunities

Endothelial to mesenchymal transition (EndMT) is a process whereby an endothelial cell undergoes a series of molecular events that lead to a change in phenotype toward a mesenchymal cell (e.g., myofibroblast, smooth muscle cell). EndMT plays a fundamental role during development, and mounting evidence indicates that EndMT is involved in adult cardiovascular diseases (CVDs), including atherosclerosis, pulmonary hypertension, valvular disease, and fibroelastosis. Therefore, the targeting of EndMT may hold therapeutic promise for treating CVD. However, the field faces a number of challenges, including the lack of a precise functional and molecular definition, a lack of understanding of the causative pathological role of EndMT in CVDs (versus being a "bystander-phenomenon"), and a lack of robust human data corroborating the extent and causality of EndMT in adult CVDs. Here, we review this emerging but exciting field, and propose a framework for its systematic advancement at the molecular and translational levels. (J Am Coll Cardiol 2019; 73: 190-209) (c) 2019 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation