Abstract 12590: Inhibition of MicroRNA-92a Enhances Angiogenesis and Cardiomyocyte Regeneration Through Integrin α5-Dependent Accumulation of Stem Cells Into the Infarcted Myocardium
Background: Regeneration of the heart after myocardial infarction (MI) may be limited by inhibition of stem cell migration to the infarcted tissue. Integrin plays a crucial role in migration of stem cells. MicroRNA-92a (miR-92a) is a negative regulator of angiogenesis and tumorigenesis. Because miR-92a targets mRNA encoding integrin α5 (ITGA5), we hypothesized that inhibition of miR-92a promotes accumulation of stem cells into the infarcted myocardium through ITGA5, thereby increasing angiogenesis and myocardial regeneration after MI.
Methods and Results: MI was created by ligation of the left coronary artery in rats. Gelatin hydrogel microsphere (GHM)-incorporated patch impregnated with antagomir-92a was placed on the surface of the infarct risk area at the time of MI. MiR-92a expression markedly increased after MI. Antagomir-92a restored ITGA5 expression in c-kit-positive (c-kitPOS) cells in the infarct border zone 48 hours after MI. Anti-ITGA5 antibodies co-impregnated with antagommir-92a abolished accumulation of c-kitPOS cells in the infarct border zone. The antagomia-92a impregnated patch increased the number of CD31-positive endothelial cells and α-actinin-positive cardiomyocytes that incorporated bromodeoxyuridine in the infarct border zone 14 days after MI. This was associated with an increase in capillary and vascular density in the infarct border zone and marked inhibition of infarct size. Consequently, left ventricular (LV) dimension was reduced, and LV ejection fraction and LV ± dp/dt were increased in the infarcted heart with the antagomir-92a impregnated patch. Anti-ITGA5 antibodies abolished angiogenesis and cardiomyogenesis conferred by the antagomir-92a impregnated patch. The patch alone or the patch impregnated with a scrambled sequence of antagomir-92a had no effect on angiogenesis, cardiomyogenesis, infarct size and LV function after MI.
Conclusions: MiR-92a is overexpressed and inhibits accumulation of stem cells into the infarct border zone. Controlled release of antagomir-92a using GHM-incorporated patch promotes accumulation of stem cells in the infarct area by restoring expression of ITGA5, enhances angiogenesis and cardiomyogenesis, and ameliorates cardiac remodeling and function after MI.
- Cardiac regeneration
- Myocardial infarction
- Regenerative medicine stem cells
- Tissue engineering
- © 2011 by American Heart Association, Inc.