Antiapoptotic mechanisms of Chinese medicine formula, Guan-Xin-Er-Hao, in the rat ischemic heart.
Considerable evidence indicates that apoptosis plays a critical role in acute myocardial infarction. We have previously shown that Guan-Xin-Er-Hao (GXEH), a Chinese medicine formula, attenuates postischemia myocardial apoptosis. The present study was designed to determine the mechanisms by which GXEH exerts its antiapoptotic effect. Adult male Sprague-Dawley rats were randomized to receive vehicle or GXEH (5 or 15 g/kg) orally 30 min before ischemia and subjected to myocardial ischemia of 3 h (apoptosis peak) or 24 h (necrosis peak) for determination of infarct size. Compared with rats receiving vehicle, those rats treated with GXEH (15 g/kg) showed significantly reduced infarct size, the reduced myocardial apoptosis, as judged by the decreases in TUNEL-positive staining (22.40 +/- 5.68% vs. 40.31 +/- 10.58%, p < 0.01), and the decrease in the degree of caspase-3 activation (82.97 +/- 10.54 vs. 159.95 +/- 9.16 mumol cleaved acetyl-Asp-Glu-Val-Asp-p-nitroanilide/mg protein, p < 0.01). Treatment with GXEH (15 g/kg) significantly reduced the release of mitochondrial cytochrome c, a primary mediator of apoptosis, the degree of caspase-9 activation, and the Bax/Bcl-2 ratio. Caspase-9 cleaves and activates caspase-3. Bax promotes apoptosis, while Bcl-2 inhibits apoptosis. Thus, the antiapoptotic mechanisms of GXEH may involve the mitochondrial cytochrome c-mediated caspase-3 activation in cardiomyocytes after acute myocardial infarction. Taken together, GXEH tilted the balance between Bax and Bcl-2 toward an antiapoptotic state, decreased mitochondrial cytochrome c release, reduced caspase-9 activation, and attenuated subsequent caspase-3 activation and postischemic myocardial apoptosis in rats. GXEH may be used as a promising agent for future treatment of cardiovascular diseases.
Zhao
Hong-Wei
HW
Laboratory of Ethnopharmacology, West China Hospital, Sichuan University, Chengdu, PR China.
Qin
Feng
F
Liu
Yi-Xia
YX
Huang
Xi
X
Ren
Ping
P
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004365:Drugs, Chinese Herbal / Q000494:pharmacology* / Q000627:therapeutic use*; D004789:Enzyme Activation / Q000187:drug effects; D008297:Male; D008516:Medicine, Chinese Traditional; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
D004365:Drugs, Chinese Herbal; C534196:guan xin II; D045304:Cytochromes c; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9