Abstract 14103: Loss of Bone Morphogenetic Protein (BMP) 9 Activity Reduces Survival and Increases Collagen Turnover via Enhanced Matrix Metalloproteinase Activity After Acute Myocardial Infarction

Abstract

Introduction: Acute myocardial infarction (AMI) is a major cause of heart failure and mortality. The extracellular matrix plays a central role in post-infarct remodeling. We recently reported that BMP9 negatively regulates cardiac fibrosis in heart failure. A functional role for BMP9 in post-infarct remodeling remains poorly defined. We hypothesize that BMP9 signaling via activin like kinase 1 (ALK1) promotes survival after AMI by negatively regulating fibrosis and limiting matrix metalloproteinase (MMP) activity. Methods: AMI was induced by left coronary artery ligation in wild type (WT), BMP9-/- and ALK-/+ mice. After 14 days, LV function was assessed using conductance catheter and myocardial BMP9 signaling pathways were studied. In vitro siRNA mediated protein knockdown in human atrial fibroblasts (AtFB) further tested this signaling pathway. Results: BMP9-/- and ALK-/+ mice had significantly reduced survival after AMI compared to WT (p=0.04 and 0.008 respectively) and was associated with an increased incidence of cardiac rupture. LV ejection fraction decreased significantly among BMP9-/- and ALK1+/- survivors compared to sham (p<0.01 for both). pSMAD3 was increased and pSMAD1 decreased in both BMP9-/- and ALK1-/+ mice after AMI. Reduced pSMAD1 expression was directly associated with increased type 1 collagen levels in BMP9-/- (R 2 =0.48, p=0.02) and ALK1-/+ (R 2 =0.42, p=0.01) mice compared to WT. LV protein levels of endoglin increased significantly in both BMP9-/- and ALK+/- compared to WT sham (p<0.01 for both) after AMI. LV levels and activity of MMP9 were increased in BMP9-/-, but not in ALK1+/-, compared to WT after AMI (p=0.02 and 0.8 respectively). Circulating biomarkers of collagen degradation:synthesis (ICTP:PINP ratio) increased significantly (p=0.02) in BMP9-/- compared to WT after AMI. BMP9 but not ALK1 knockdown in AtFBs increased expression and activity of MMP9 (p=0.01 and 0.3 respectively). Conclusions: These findings identify a novel functional role for BMP9 and ALK1 as determinants of post-infarct survival and cardiac remodeling and further suggest that loss of BMP9-ALK1 signaling increases collagen degradation and turnover. BMP9/ALK1 signaling may be a novel target of therapy for post-infarct remodeling and survival.