Abstract 1267: Essential Roles of PDK-1 in the Regulation of β-Adrenergic Response and Cell Survival in the Hearts.
Background: The 3-phosphoinositide-dependent kinase-1 (PDK-1) is a ubiquitously expressed kinase that plays important roles in mediating a variety of effects of growth factors on cells. In particular, PDK-1 is crucial in the phosphoinositide 3-kinase(PI3-K) signaling pathway through phosphorylating and activating several kinases including Akt and p70 S6 kinase. Although PDK-1 was reported to be important for the regulation of cardiomyocyte size, the significance of PDK-1 in the heart was not well understood.
Methods and Results: To elucidate the roles of PDK-1 in the postnatal heart, we generated tamoxifen-inducible heart specific PDK-1 knockout mice (PDK-1 MerCre) and disrupted PDK-1 gene at the age of 10 weeks. PDK-1 MerCre died of heart failure from 5 to 15 weeks after dispruption of PDK-1. At 1 week after PDK-1 disruption cardiomyocyte size was not reduced, but left ventricular systolic dysfunction was already observed. Langendorff perfusion indicated impairment of isoproterenol responsiveness in PDK-1 MerCre hearts. PI3-K γ activity was enhanced, which might lead to β-adrenergic receptor desensitization by activating G-protein coupled receptor kinase 2. TUNEL staining and immunohistochemical staining for cleaved caspase-3 displayed an extreme increase in apoptotic cardiomyocytes 1 week after inactivation of PDK-1. PDK-1 MerCre hearts showed reduction of SGK activity, upregulation of bax protein and endoplasmic reticulum stress signals, which were potentially involved in cardiomyocyte apoptosis. Finally, the expression levels of PDK-1 protein were decreased in murine hearts of post-myocardial infarction cardiomyopathy and adriamycin-induced cardiomyopathy, suggesting that PDK-1 might be a promising molecular target for treatment of heart failure.
Conclusions: These results suggest that PDK-1 is essential for normal cardiac function by preserving responsiveness to β-adrenergic stimulation and by preventing cardiomyocyte apoptosis.