| Myocardial ischemic pretreatment is referred to short-term ischemia which can reduce the myocardial infarction area for the following long-time ischemia significantly. At present, the phenomenon by pretreatment is common: whether at organ level or cell level, in vivo or in vitro, involving in various types of cells including human cardiac cells. Myocardial ischemic pretreatment is a powerful cardia myocardioprotective modus and endogenous preadaptation to myocardial ischemic.The classic myocardial ischemic pretreatment need to block blood current temporarily in clinical application.it is not refer to the most application safely .For the above ,People were seeking some drugs to induce myocardial ischemic pretreatment. The study of Garlid showed that mitochondrial KATP channel (MitoKATP channel) played a central role in myocardial protection by pretreatment, which was not only the end effector in myocardial protection by pretreatment1 but also an important trigger molecule . Mitochondria are the important target for myocardial protection, opening of MitoKATP can preserve the structure and function of cardiac mitochondria under hypoxia, as well as possesses the protection under myocardial hypoxia, ischemia and reperfusion injuryAdenosine receptors-protein kinase C (PKC)-KATP channel is an important signal pathway to ischemic pretreatment. Many studies indicated that drug pretreatment including adenosine and bradykinin, could also simulate myocardial ischemic pretreatment and could prevent myocardial ischemic injury, making clinical use of drugs to reduce myocardial infarction in patients with cardiac cell death become possible. However, some articles reported that long-time agitation to adenosine receptor or PKC with specific agonists could cause the myocardial protective effect of ischemic and drug pretreatment to disappear. Some studies showed that the mechanism might be related to the down-regulated expression of signaling protein in preprocessed signaling pathway caused by prolonged use of pretreatment drugs.So it is doubtful whether long-time use of the above-mentioned drugs can bring long-term and stable myocardial protective effects, and will there come out new problems in clinical myocardial protection during the application of drug pretreatment.In order to observe the effect for long-term DZ pretreatment on rats Myocardioprotective effect and its possible mechanism ,In our study, injection of DZ, a MitoKATP channel-specific agent, was administered to SD rats for a long time and detect the mitochondrial respiratory function , membrane potential and cTnI.on the of isoprenaline induced myocardial inhury model .Besides, we extracted mitochondrial inner membrane protein, and screened the down-regulated protein in the mitochondrial inner membrane using 2-dimensional fluorescence difference gel electrophoresis (2D-DIGE) and tandem mass spectrometry for protenome analysis. The mechanism of disappeared myocardial protective effect for long-term DZ pretreatment was investigated to explore MitoKATP associated proteins. The major findings and conclusions were as follows:1. The myocardial ischemic rat model caused by single subcutaneous injection of isoproterenol (ISO) (50mg?kg–1), could demonstrate myocardial injury by ISO well. After 3 d 20mg?kg-1?d-1consecutive intraperitoneal injection, the myocardial protective effect by pretreatment was significant, resisting myocardial ischemia, and relieving pathological changes.2. Generally, consecutive intraperitoneal injection of DZ (20mg?kg–1?d–1) for 6 w could diminish the myocardial protective effect caused by DZ pretreatment, and could inhibit mitochondrial respiratory function obviously, secret cTnI in great quantity, proving that it was successful in modeling of disappeared myocardial protective effect for long-term DZ pretreatment.3. In rat model of disappeared myocardial protective effect for long-term DZ pretreatment, the gene and protein expression of myocardial membrane KATP channel SUR2A subunits had no significant changes. So its underlying mechanism might be not correlated with opening of myocardial membrane KATP channel, but related with down-regulated expression of MitoKATP channel associated proteins.4. Based on rat model of disappeared myocardial protective effect for long-term DZ pretreatment, 2D-DIGE was used to screen the differential expression of 15 protein points, 8 proteins of them was identified by mass spectrometry. The expression of heat shock protein 60 (HSP60) and mitochondrial ATP synthaseαchain was up-regulated. While, the expression of following proteins was down-regulated: Ubiquinol-cytochrome c reductase core protein 1(Uqcrc1), subunit d of mitochondrial ATP synthase, Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-UO), Prohibitin and mitochondrial ATP synthaseβchain, all of which were located in the mitochondrial inner membrane, as well as were the important elements of ischemic and drug pretreatment. The down-regulated proteins might play an important role in the disappeared myocardial protective effect for long-term DZ pretreatment.
|
PDF Full Text Request