Abstract 784: PDK-1 is Required for Regulation of Cell Size, Beta-Adrenergic Response and Cell Survival in the Heart.
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. PDK-1 is in particular crucial in the phosphoinositide 3-kinase(PI3-K) signaling pathway through phosphorylating and activating several kinases including Akt, p70 S6 kinase, mTOR, SGK-1, and certain isoforms of protein kinase C. Here, we investigated the pathophysiological role of PDK-1 in the heart using two types of PDK-1 conditional knockout mice. First we generated muscle specific PDK-1 knockout mice (PDK-1 MCKCre) by crossing mice harboring a floxed Pdk-1 allele with mice expressing Cre recombinase under the control of the muscle creatine kinase gene promoter which induced striated muscle-specific Cre expression just prior to birth. PDK1 MCKCre died by 8 weeks of age because of symptomatic heart failure. PDK-1 MCKCre exhibited a marked reduction in heart mass and in the surface area of isolated cardiomyocytes. Next, to examine the role of PDK-1 in left ventricular(LV) function in detail, we generated Tamoxifen-inducible heart specific PDK-1 knockout mice (PDK-1 MerCre) by using MerCreMer transgenic mice, 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, LV systolic dysfunction was already revealed by echocardiography, and Langendorff perfusion indicated impairment of isoproterenol responsiveness in PDK-1 MerCre hearts. TUNEL staining and immunohistochemical staining for cleaved caspase-3 showed an extreme increase in apoptotic cardiomyocytes 1 week after inactivation of PDK-1. Therefore, these results suggest that PDK-1 plays essential roles in the regulation of cell size, cardiac response to beta-adrenergic stimulation, and cardiomyocyte cell survival by preventing apoptosis.