PDK1 coordinates survival pathways and beta-adrenergic response in the heart.
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.
Department of Cardiovascular Science and , Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
Kaoru
K
Ito
Hiroshi
H
Akazawa
Masaji
M
Tamagawa
Kensuke
K
Furukawa
Wataru
W
Ogawa
Noritaka
N
Yasuda
Yoko
Y
Kudo
Chien-hui
CH
Liao
Rie
R
Yamamoto
Toshiaki
T
Sato
Jeffery D
JD
Molkentin
Masato
M
Kasuga
Tetsuo
T
Noda
Haruaki
H
Nakaya
Issei
I
Komuro
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D017209:Apoptosis; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015996:Survival Rate; D013629:Tamoxifen / Q000494:pharmacology
D064413:3-Phosphoinositide-Dependent Protein Kinases; D054769:G-Protein-Coupled Receptor Kinase 2; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D019253:Proto-Oncogene Proteins c-bcl-2; D011943:Receptors, Adrenergic, beta; D013629:Tamoxifen; C578564:Pdpk1 protein, mouse