Objective: β-catenin is a transcriptional regulator of several genes involved in survival and proliferation. We investigated the role of β-catenin and involved mechanisms in cardiomyocytes and fibroblasts, and whether β-catenin gene transfer could reduce myocardial infarction (MI) size.
Methods and Results: To enforce b-catenin activity, we produced non-phosphorylatable constitutively active mutant of β-catenin plasmid and the recombinant adenovirus-β-catenin-mutant (Ad-catenin) was successfully constructed. Transfected cells were determined by the co-expression of GFP and adenovirus encoding GFP (Ad-GFP) was used as control viral transfection. In vitro, the effects of constitutively active β-catenin gene transfer were examined on cardiomyocytes and fibroblasts. The transfection of Ad-catenin decreased serum deprivation induced apoptosis in cardiomyocytes and cardiac fibroblasts with increased expression of anti-apoptotic protein, survivin. Although overexpression of β-catenin increased the percentage of cells in the S phase with enhanced expression of cyclin D1 and E2 in both cell types, cell number increased only in fibroblasts. On the contrary, the effect of β-catenin on hypertrophy was more prominent in cardiomyocytes, which showed much more increase of cell size and polyploid cells. Furthermore, transfection of Ad-catenin enhanced the expression of vascular endothelial growth factor (VEGF) in cardiomyocytes and fibroblasts and α-smooth muscle actin in fibroblasts, which meant the transformation into myofibroblasts. In vivo, we transferred Ad-catenin into the border zone of rat MI model. Better preservation of anterior regional wall motion and systolic function was observed, and MI size was smaller in Ad-catenin group compared with Ad-GFP. Apoptosis decreased, and proliferating cardiomyocytes and myofibroblasts were more frequently observed in Ad-catenin group. Immunohistochemistry showed more capillaries and VEGF expression in the Ad-catenin group than the Ad-GFP group.
Conclusions: These data suggest that β-catenin plays an important role in the healing process after MI through its control of survival and cell cycle as well as enhanced expression of VEGF.
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