RP105 Protects Against Apoptosis in Ischemia/Reperfusion-Induced Myocardial Damage in Rats by Suppressing TLR4-Mediated Signaling Pathways.
BACKGROUND
Myocardial apoptosis is heavily implicated in the myocardial damage caused by ischemia-reperfusion (I/R). Toll-like receptor 4 (TLR4) is a potent inducer of these apoptotic cascades. In contrast, the radioprotective 105 kDa protein (RP105) is a specific negative regulator of TLR4 signaling pathways. However, the precise mechanisms by which RP105 inhibits myocardium apoptosis via TLR4-associated pathways during I/R is not fully understood.


METHODS
We utilized a rat model of myocardial ischemic reperfusion injury (MIRI). Animals were pre-treated with Ad-EGFP adenovirus, Ad-EGFP-RP105 adenovirus, saline, or nothing (sham). After three days, rats underwent a 30min left anterior descending coronary artery occlusion and a 4h reperfusion. Mycardial tissue was assessed by immunohistochemistry, TUNEL-staining, Western blot, quantitative RT-PCR, and a morphometric assay.


RESULTS
RP105 overexpression resulted in a reduction in infarct size, fewer TUNEL-positive cardiomyocytes, and a reduction in mitochondrial-associated apoptosis cascade activity. Further, RP105 overexpression repressed I/R-induced myocardial injury by attenuating myocardial apoptosis. This was mediated by inhibiting TLR4 activation and the phosphorylation of P38MAPK and the downstream transcription factor AP-1.


CONCLUSIONS
RP105 overexpression leads to the de-activation of TLR4, P38MAPK, and AP-1 signaling pathways, and subsequently represses apoptotic cascades and ensuing damage of myocardial ischemic reperfusion. These findings may become the basis of a novel therapeutic approach for reducing of cardiac damage caused by MIRI.
Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang, China.
Jun
J
Yang
Xin
X
Guo
Jian
J
Yang
Jia-Wang
JW
Ding
Song
S
Li
Rui
R
Yang
Zhi-Xing
ZX
Fan
Chao-Jun
CJ
Yang
D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis; D002316:Cardiotonic Agents; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D015854:Up-Regulation
D015703:Antigens, CD; D002316:Cardiotonic Agents; D051197:Toll-Like Receptor 4; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins