Abstract 12913: microRNA-17 Targets TIMP-1 and TIMP-2 to Accelerate Cardiac Matrix Remodeling After Infarction
Introduction: The effects of microRNA-17 (miR-17) have been reported for some disease processes, but its regulation of cardiac matrix remodeling after myocardial infarction (MI) has not been extensively investigated. Our pilot study demonstrated that miR-17 overexpression accelerated myocardial dilation. Here we investigated the possible mechanism of matrix modulation in mice overexpressing miR-17.
Methods/Results: Adult mice underwent coronary artery ligation to generate an MI, and endogenous miR-17 was found to be significantly (p<0.05) upregulated in the infarct and border zone (n=6/group). To identify the primary gene target for miR-17, we generated transgenic mice overproducing miR-17 in the myocardium. The miR-17 mice had greater ventricular dysfunction (decreased fractional shortening) 7 days after MI (p<0.01). Pressure-volume analysis demonstrated dramatically reduced end-systolic pressure and elastance, stroke work, and pre-recruitable stroke work in miR-17 vs. wild-type mice (n=10/group, p<0.01) 7 and 14 days post-MI. Histological analysis of miR-17 myocardium revealed increased scar formation and apoptosis, an imbalance in the collagen type I/III ratio (toward more type I), and reduced ventricular wall thickness and angiogenesis. Of particular interest, the expression of TIMP-1 and TIMP-2 (tissue inhibitors of metalloproteinases) in miR-17 hearts was significantly repressed, concurrently with enhanced MMP9 (matrix metalloproteinase 9) proteolytic activity, which was replicated in vitro by transfecting cells with miR-17 mimic RNA vs. scrambled control RNA. In vitro and in vivo mechanistic studies demonstrated that miR-17 targeted the 3’-UTR of TIMP-2 and protein coding region of TIMP-1, resulting in their inhibition and consequent elevation of MMP9 activity. Blockade of endogenous miR-17 via the in vivo delivery of a miR-17 antagomir enhanced TIMP-1 and TIMP-2 protein expression, decreased MMP9 activity, reduced infarct size, and improved cardiac function.
Conclusions: Our study provides novel mechanistic data indicating how miR-17 regulates cardiac matrix remodeling. These insights could permit the development of therapeutic approaches using miR-17 inhibitors to prevent heart failure after an extensive MI.
- © 2011 by American Heart Association, Inc.