| Literature DB >> 19429709 |
Kaoru Ito1, Hiroshi Akazawa, Masaji Tamagawa, Kensuke Furukawa, Wataru Ogawa, Noritaka Yasuda, Yoko Kudo, Chien-hui Liao, Rie Yamamoto, Toshiaki Sato, Jeffery D Molkentin, Masato Kasuga, Tetsuo Noda, Haruaki Nakaya, Issei Komuro.
Abstract
The 3-phosphoinositide-dependent kinase-1 (PDK1) plays an important role in the regulation of cellular responses in multiple organs by mediating the phosphoinositide 3-kinase (PI3-K) signaling pathway through activating AGC kinases. Here we defined the role of PDK1 in controlling cardiac homeostasis. Cardiac expression of PDK1 was significantly decreased in murine models of heart failure. Tamoxifen-inducible and heart-specific disruption of Pdk1 in adult mice caused severe and lethal heart failure, which was associated with apoptotic death of cardiomyocytes and beta(1)-adrenergic receptor (AR) down-regulation. Overexpression of Bcl-2 protein prevented cardiomyocyte apoptosis and improved cardiac function. In addition, PDK1-deficient hearts showed enhanced activity of PI3-Kgamma, leading to robust beta(1)-AR internalization by forming complex with beta-AR kinase 1 (betaARK1). Interference of betaARK1/PI3-Kgamma complex formation by transgenic overexpression of phosphoinositide kinase domain normalized beta(1)-AR trafficking and improved cardiac function. Taken together, these results suggest that PDK1 plays a critical role in cardiac homeostasis in vivo by serving as a dual effector for cell survival and beta-adrenergic response.Entities:
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Year: 2009 PMID： 19429709 PMCID： PMC2688981 DOI： 10.1073/pnas.0900064106
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205