Overexpression of Shp-2 attenuates apoptosis in neonatal rat cardiac myocytes through the ERK pathway.

During cardiac ischemia and end-stage heart disease, a large number of cardiac cells are apoptotic, and therefore, heart function is impaired. Although the role of Shp-2 in cell survival has been reported, its regulation of cardiac apoptosis is still undetermined. To better understand the potential role of Shp-2 in apoptosis, cell death was determined in serum-depleted cardiomyocytes. Shp-2 was inhibited by NSC87877, and apoptosis, Cyt C release and caspase 3 activation were determined. To evaluate the notion that Shp-2 plays a role in survival stimulation, wild-type and gain-of-function mutant Shp-2 adenoviruses were infected into neonatal cardiomyocytes, and ERK activation was examined. Finally, the MEK inhibitor U0126 was utilized to block the ERK pathway and determine the role of Shp-2 in this pathway. We found that Shp-2 inhibition enhanced apoptosis via regulation of mitochondrial Cyt C release and activation of caspase 3. Overexpression of Shp-2 inhibited apoptosis through activation of ERK. The MEK inhibitor U0126 abolished Shp-2's effect on apoptosis in cardiomyocytes. Our results have revealed that Shp-2 functions as an intracellular inhibitor of apoptosis. These data provide insight into the pathogenesis and the therapeutic strategies of heart diseases.