Abstract 16540: MicroRNA 145 Prevents Infarct Scar Expansion and May be a New Target for Cardiac Restoration After Myocardial Infarction
Introduction: Progressive heart failure following an MI results from adverse cardiac remodeling with infarct expansion and ventricular dilatation. The prevention of this process requires the identification of new contributing mechanisms and new therapeutic targets. MicroRNA 145 (miR-145) regulates the differentiation of vascular smooth muscle cells (VSMCs) and recent studies have shown that miR-143/145 knockout (KO) mice have a severe reduction in the number of contractile VSMCs and an increase in synthetic VSMCs.
Hypothesis: We hypothesized that miR-145 promotes differentiation of cardiac fibroblasts to myofibroblasts and miR-145 KO is associated with decreased myofibroblast formation and increased adverse cardiac remodeling after MI.
Methods and Results: Using real time qPCR, we found that miR-145 expression in the scar region decreased 3 days post-MI, then increased gradually from Days 7-14, and was restored 28 days post-MI in wild type (WT) mice. In miR-145 KO mice after MI, cardiac function declined more rapidly than WT mice. Fractional shortening was significantly lower at 28 days post-MI in KO (17.0±1.6%) than WT (21.4±2.6%) mice (n=10, p<0.01). LV internal diastolic (LVIDd) and systolic dimension (LVIDs) were both significantly higher in KO than WT mice 28 days post-MI (p<0.01). Scar size was significantly larger (p<0.01) in KO than WT mice at Day 28 post-MI. The α-smooth muscle actin (α-SMA) positive area in the whole heart at Day 7 post-MI was significantly greater in WT than KO mice (WT: 19.3±2.6%; KO: 4.5±0.6%, p=0.005). The migration rate (wound-scratch assay) of cardiac fibroblasts harvested from miR-145 KO mice was 32% lower than that of WT mice. Quantification of collagen I and α-SMA protein levels and wound contraction measured with a collagen gel contraction assay revealed that the transdifferentiation of cardiac fibroblasts into myofibroblasts was lower (p<0.05) in KO than WT mice.
Conclusions: miR-145 contributes to infarct scar contraction in WT mice and the absence of miR-145 results in greater infarct scar thinning and dilatation. Augmentation of miR-145 could be an attractive target to prevent adverse cardiac remodeling after MI by enhancing the phenotypic differentiation of cardiac fibroblasts to myofibroblasts.
Author Disclosures: H. Song: None. S. He: None. S. Li: None. Z. Shao: None. J. Wu: None. G. Du: None. J. Wu: None. W. Yin: None. J. Li: None. R.D. Weisel: None. R. Li: Research Grant; Significant; Canadian Institutes of Health Research Founation grant (332652).
- © 2016 by American Heart Association, Inc.