Studies On The Mechanism Of Dingxinrecipe In Preventing And Treating Myocarydial Ischemic And Reperfusion Injury

ABSTRACTMyocardial ischemia and reperfusion(MI/R) injury has the greatly meaning of physiopatholgy in the ischemic heart disease and heart surgery. But its pathogeny mechanisms remains incompletely elucidated. At present, reactive oxygen species(ROS) damage and calcium overload are essential mechanisms of MIIR injury . Recently , TNF-a has been appreciated as an important mediator of MI/R damage.So anti-TNF-a therapy may provide a new method to preventing and treatment of MI/R injury. Considerable information exists concerning the mechanisms by which LPS induces TNF-a production ; however ,Iittle is known about the mechanisms of ischemic and reperfi.ision induced cardiac TNF-ci production. Mitogen-activated protein kinases (MAPK) which is one of the important signal transduction systems in organism, is involved in many cellular processes. MAPK was proved to play crucial role in signal transduction of MIIR. We found that Dingxinrecipe (DXR) had protective effect on MIIR injury. But its mechanism is still not clear.In this paper, we studied the role of ROS , TNF-cL and MAPK in MI/R injury ,and studied the mechanisms of DXR in preventing and treating MIIR injury. We hope the research can provide theoretic and experimental evidence for exertion of DXR. For this purpose, fist , we researched the pathogeny mechanisms of MI/R injury and mechanisms of protective effect of DXR by the rat model of MIIR. Second ,we investigated the injury of cultured rat cardiomyocytes by Hydrogen Peroxide (H202) and the influence of DXR on it. Third , we studied the mechanisms of TNF-ct production of cardiomyocytes induced by H202.The results showed that, MIIR caused arrhythmias ,descent of the mean arterial pressure (MAP) and heighten of serumal LDH. Meanwhile, the-4-myocardium of reperfusion was shown to increase contents of myocardial TNF-a, to decrease the activities of GSH-Px ,to increase MDA contents and activities of P38 MAPK. DXR can decrease the incidence of arrhythmia induced by ischemia and reperfusion, increase the activities of GSH-Px decrease the MDA and TNF-a contents and the activities of myocardial p38 MAPK .DXR can protect the cardiomyocytes from the injury induced by H202 too. H202 caused TNF-c~ production of cardiomyocytes in a concentration- and time- dependent manner. The stimulating role of H202 to TNF-cL production of cardiomyocytes were markedly inhibited by SB203 580 andlor cotransfection of 1KB eDNA which inhibited activities of NF-KB.We concluded that the ROS , TNF-ct and p38 MAPK played important role in the pathogeny mechanisms of Ml/R injury. DXR had protective effects on MIIR injury by its antiperoxidative effect, decrease of myocardial TNF-c~ production and regulation of p38 MAPK signal transduction. MI/R induced cardiac TNF-cL production may be mediated by P38 MAPK pathway and activation of NF-KB which are activated by ischemia and reperfusionproduced reactive oxygen species (H202).