c-Jun N-terminal kinases mediate reactivation of Akt and cardiomyocyte survival after hypoxic injury in vitro and in vivo.
Akt is a central regulator of cardiomyocyte survival after ischemic injury in vitro and in vivo, but the mechanisms regulating Akt activity in the postischemic cardiomyocyte are not known. Furthermore, although much is known about the detrimental role that the c-Jun N-terminal kinases (JNKs) play in promoting death of cells exposed to various stresses, little is known of the molecular mechanisms by which JNK activation can be protective. We report that JNKs are necessary for the reactivation of Akt after ischemic injury. We identified Thr450 of Akt as a residue that is phosphorylated by JNKs, and the phosphorylation status of Thr450 regulates reactivation of Akt after hypoxia, apparently by priming Akt for subsequent phosphorylation by 3-phosphoinositide-dependent protein kinase. The reduction in Akt activity that is induced by JNK inhibition may have significant biological consequences, as we find that JNKs, acting via Akt, are critical determinants of survival in posthypoxic cardiomyocytes in culture. Furthermore, in contrast to selective p38-mitogen-activated protein kinase inhibition, which was cardioprotective in vivo, concurrent inhibition of both JNKs and p38-mitogen-activated protein kinases increased ischemia/reperfusion injury in the heart of the intact rat. These studies demonstrate that reactivation of Akt after resolution of hypoxia and ischemia is regulated by JNKs and suggest that this is likely a central mechanism of the myocyte protective effect of JNKs.
Shao
Zhili
Z
Molecular Cardiology, Tufts-New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA.
Bhattacharya
Kausik
K
Hsich
Eileen
E
Park
Larry
L
Walters
Brian
B
Germann
Ursula
U
Wang
Yow-Ming
YM
Kyriakis
John
J
Mohanlal
Ramon
R
Kuida
Keisuke
K
Namchuk
Mark
M
Salituro
Francesco
F
Yao
Yung-mae
YM
Hou
Wei-min
WM
Chen
Xin
X
Aronovitz
Mark
M
Tsichlis
Philip N
PN
Bhattacharya
Susmita
S
Force
Thomas
T
Kilter
Heiko
H
D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D004789:Enzyme Activation; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases