Bone Morphogenetic Protein-9 (BMP9) is Required for Survival and Limits Left Ventricular Matrix Metalloproteinase Activity After Acute Myocardial Infarction

Abstract

<h3>Purpose</h3> Reorganization of extracellular matrix is a major determinant of short and long term wound healing after acute myocardial infarction (AMI), which includes central roles for matrix metalloproteinases (MMP) and collagen turnover. We recently identified that bone morphogenetic protein (BMP)-9 is a novel endogenous inhibitor of cardiac fibrosis in murine models of pressure overload induced heart failure. We hypothesized that BMP9 regulates MMP activity and is required for survival after AMI. <h3>Methods</h3> WT or BMP9-/- mice were subjected to left anterior descending artery ligation and animals recovered for 2 weeks. Left ventricular (LV) function was assessed using conductance catheter and LV tissue was harvested for molecular analysis in animals surviving to two weeks. To further assess a functional role for BMP9, in vitro studies were performed using human atrial fibroblasts (H-Atr-Fb). <h3>Results</h3> Compared to WT controls BMP9-/- mice had reduced survival (94.4% v 66.7%, p=0.04) and tissue necropsy showed a high rate of cardiac rupture among BMP9-/- mice (BMP9-/- 80%, WT 0%). Ejection fraction and stroke work were reduced and both LV end systolic and diastolic volumes were increased in WT and BMP9-/- mice after AMI. Compared to WT, SMAD3 signaling was increased (p=0.001) and SMAD1 signaling reduced (p=0.03) in BMP9-/- mice after AMI. Compared to WT, BMP9-/- mice had higher LV protein levels of endoglin, Type 1 collagen and periostin. We further observed significantly higher LV MMP9 levels and activity in BMP9-/- compared to WT sham (p=0.003) and WT MI (p=0.02) mice after AMI . Compared to WT, BMP9-/- mice exhibited an increased ratio of circulating markers of collagen degradation and synthesis (ICTP:PINP) after AMI (p=0.02). In H-Atr-Fb, siRNA mediated knockdown of BMP9 increased protein levels of Type I collagen (p<0.05) and MMP9 (p=0.04) and increased MMP9 activity (p=0.003). <h3>Conclusion</h3> We report that BMP9 is necessary for survival after AMI and identify a novel functional role of BMP9 as a negative regulator of MMP9 activity and collagen synthesis in the LV during AMI. These findings suggest that BMP9 may be an important novel target of therapy to improve myocardial recovery and survival after AMI.