Abstract 11124: Exogenous AMPK Activation Improves Myofibroblast Maturation and Scar Formation in the Infarcted Aging Heart
We have previously demonstrated that cardiac repair after myocardial infarct (MI) is associated with an endogenous pool of CD44+CD45- multipotential mesenchymal stem cells that rapidly proliferates within the infarct a few days after MI. These cells differentiate into collagen secreting fibroblasts that form a scar and later mature into myofibroblasts expressing alpha smooth muscle actin (α-SMA) that contract the scar and prevent infarct expansion and ventricular dilatation. Fibroblast-to-myofibroblast maturation is mediated by TGF-β1 signaling. Our studies demonstrate age-dependent defects in murine MI repairs with poorly organized scar. We have also reported that fibroblasts derived from aged murine hearts are defective; they matured poorly into myofibroblasts as a result of reduced expression of TGF-β receptor I. Interestingly, in vitro, we were able to rescue the aged myofibroblast maturation through activation of AMP kinase (AMPK) and its downstream kinase p38MAPK (non canonical TGF-β signaling). Thus, we hypothesized that in vivo activation of AMPK might improve myofibroblast maturation in the aged infarcted heart. 14 month old C57BL/6 mice were injected with AICAR (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, 0.5 mg/g of body weight/day) an AMPK activator or saline for up to 7 days. Animals were subjected to occlusion (1h) and reperfusion of the LAD. Hearts were isolated at 5 and 7 days and 24 hours after last dose of AICAR. Moreover, immunoblot analysis of whole heart lysates showed increased phosphorylation/activation of AMPK and expression of α-SMA by two fold in hearts isolated from AICAR-treated mice. Immunofluorescence staining revealed that AICAR-treated mice had improved cardiac repair compared to control animals as demonstrated by increased collagen synthesis and a higher density of CD44+αSMA+ cells within a scar. As postulated, this was accompanied by an increased density of phosphorylated/activated p38MAPK+CD44+CD45- myofibroblasts in the scar. Thus our in vivo data support our in vitro findings that AMPK activation in mesenchymal stem cells improves myofibroblast maturation and scar formation in the aged heart.
- © 2012 by American Heart Association, Inc.