MG53 constitutes a primary determinant of cardiac ischemic preconditioning.
BACKGROUND
Ischemic heart disease is the greatest cause of death in Western countries. The deleterious effects of cardiac ischemia are ameliorated by ischemic preconditioning (IPC), in which transient ischemia protects against subsequent severe ischemia/reperfusion injury. IPC activates multiple signaling pathways, including the reperfusion injury salvage kinase pathway (mainly PI3K-Akt-glycogen synthase kinase-3beta [GSK3beta] and ERK1/2) and the survivor activating factor enhancement pathway involving activation of the JAK-STAT3 axis. Nevertheless, the fundamental mechanism underlying IPC is poorly understood.


RESULTS
In the present study, we define MG53, a muscle-specific TRIM-family protein, as a crucial component of cardiac IPC machinery. Ischemia/reperfusion or hypoxia/oxidative stress applied to perfused mouse hearts or neonatal rat cardiomyocytes, respectively, causes downregulation of MG53, and IPC can prevent ischemia/reperfusion-induced decrease in MG53 expression. MG53 deficiency increases myocardial vulnerability to ischemia/reperfusion injury and abolishes IPC protection. Overexpression of MG53 attenuates whereas knockdown of MG53 enhances hypoxia- and H(2)O(2)-induced cardiomyocyte death. The cardiac protective effects of MG53 are attributable to MG53-dependent interaction of caveolin-3 with phosphatidylinositol 3 kinase and subsequent activation of the reperfusion injury salvage kinase pathway without altering the survivor activating factor enhancement pathway.


CONCLUSIONS
These results establish MG53 as a primary component of the cardiac IPC response, thus identifying a potentially important novel therapeutic target for the treatment of ischemic heart disease.
Institute of Molecular Medicine, Peking University, Beijing, China.
Chun-Mei
CM
Cao
Yan
Y
Zhang
Noah
N
Weisleder
Christopher
C
Ferrante
Xianhua
X
Wang
Fengxiang
F
Lv
Yi
Y
Zhang
Ruisheng
R
Song
Moonsun
M
Hwang
Li
L
Jin
Jiaojiao
J
Guo
Wei
W
Peng
Geng
G
Li
Miyuki
M
Nishi
Hiroshi
H
Takeshima
Jianjie
J
Ma
Rui-Ping
RP
Xiao
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D033921:Vesicular Transport Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
D002352:Carrier Proteins; C538824:MG53 protein, mouse; D008565:Membrane Proteins; D009124:Muscle Proteins; C000604080:TRIM72 protein, rat; D033921:Vesicular Transport Proteins