PDK1 coordinates survival pathways and β-adrenergic response in the heart

被引：39

作者：

Ito, Kaoru ^{[1
]}

Akazawa, Hiroshi ^{[1
]}

Tamagawa, Masaji ^{[2
]}

Furukawa, Kensuke ^{[3
]}

Ogawa, Wataru ^{[3
]}

Yasuda, Noritaka ^{[1
]}

Kudo, Yoko ^{[1
]}

Liao, Chien-hui ^{[1
]}

Yamamoto, Rie ^{[1
]}

Sato, Toshiaki ^{[2
]}

Molkentin, Jeffery D. ^{[4
]}

Kasuga, Masato ^{[3
]}

Noda, Tetsuo ^{[5
]}

Nakaya, Haruaki ^{[2
]}

Komuro, Issei ^{[1
]}

机构：

[1] Chiba Univ, Grad Sch Med, Dept Cardiovasc Sci & Med, Chuo Ku, Chiba 2608670, Japan

[2] Chiba Univ, Grad Sch Med, Dept Pharmacol, Chuo Ku, Chiba 2608670, Japan

[3] Kobe Univ, Grad Sch Med, Dept Internal Med, Div Endocrinol Diabet & Metab,Chuo Ku, Kobe, Hyogo 6500017, Japan

[4] Univ Cincinnati, Childrens Hosp, Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA

[5] Japanese Fdn Canc Res, Inst Canc, Dept Cell Biol, Koto Ku, Tokyo 1358550, Japan

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 21期

关键词：

AGC kinase; apoptosis; heart failure; receptor internalization; INDUCED GLUCOSE-UPTAKE; PHOSPHOINOSITIDE; 3-KINASE; PRESSURE-OVERLOAD; CARDIAC MYOCYTES; MOUSE MODEL; FAILURE; PROTEIN; DEFICIENCY; EXPRESSION; KINASE-1;

D O I：

10.1073/pnas.0900064106

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：8689 / 8694

页数：6

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