XXXX promotes survival of cardiomyocytes in vitro and protects against @entity63 -reperfusion injury in @entity19 heart.

@entity63 @entity19 @entity2307 @entity1188 @entity1994 @entity7424
BACKGROUND: @entity7424 has been shown to protect myocardium against death in animal models of @entity1188 and @entity63 -reperfusion injury. In the present study, we investigated the role of the @entity7424 -regulated protein kinase @entity1994 in cardiac myocyte survival in vitro and in vivo. METHODS AND RESULTS: @entity7424 promoted survival of cultured cardiomyocytes under conditions of serum deprivation in a dose-dependent manner but had no effect on cardiac fibroblast survival. The cytoprotective effect of @entity7424 on cardiomyocytes was abrogated by the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor @entity2307 . @entity2307 had no effect on cardiomyocyte viability in the absence of @entity7424 . @entity7424 -mediated cytoprotection correlated with the @entity2307 -sensitive induction of @entity1994 protein kinase activity. To examine the functional consequences of @entity1994 activation in cardiomyocyte survival, replication-defective adenoviral constructs expressing wild-type, dominant-negative, and constitutively active @entity1994 genes were constructed. Transduction of dominant-negative @entity1994 blocked @entity7424 -induced survival but had no effect on cardiomyocyte survival in the absence of @entity7424 . In contrast, transduction of wild-type @entity1994 enhanced cardiomyocyte survival at subsaturating levels of @entity7424 , whereas constitutively active @entity1994 protected cardiomyocytes from apoptosis in the absence of @entity7424 . After transduction into the @entity19 heart in vivo, constitutively active @entity1994 protected against myocyte apoptosis in response to @entity63 -reperfusion injury. CONCLUSIONS: These data are the first documentation that @entity1994 functions to promote cellular survival in vivo, and they indicate that the activation of this pathway may be useful in promoting myocyte survival in the diseased heart.
