Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 21, Pages 8689-8694Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0900064106
Keywords
AGC kinase; apoptosis; heart failure; receptor internalization
Categories
Funding
- Japanese Ministry of Education, Science, Sports, and Culture, and Health
- Labor Sciences Research Grants
- Japan Intractable Diseases Research Foundation
- Kowa Life Science Foundation
- Takeda Science Foundation
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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-K gamma, leading to robust beta(1)-AR internalization by forming complex with beta-AR kinase 1 (beta ARK1). Interference of beta ARK1/PI3-K gamma 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.
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