| Ischemia-reperfusion (I/R) injury of myocardium is a serious complication for treatment of MI and has always been a tough problem in the cure for myocardial ischemia for years. By far, there is neither dramatic advance nor systemic methods to treat I/R injury due to the exogenous mechanism for it, though many new drugs and methods have been examined. Therefore, the purpose for treatment of I/R injury has turned to cell's self-protection graduely—ischemia preconditioning, to enhance the endurance of cardiomyocytes to ischemia or I/R injury. Investigations suggest that IPC is one of the best methods to attenuate I/R injury. However, it is difficult to practice it in clinic because of its damage to human. So it is inevitable that pharmacologic preconditioning (PPC) is brought about finally. The mechanism of PPC-like is to trigger the endogenous mechanism against ischemia or I/R injury by drug substituting ischemic stimulation or caused directly in tissues or cells. There is premising that mediating the endogenous defense system and improving the endurance of cardiac cells to hypoxia may become the mechanism of new drugs protecting tissues from I/R injury.Such drugs as pioglitazone and roglitazone etc. belonging to thiazolidinediones (TZDs) are not only agonist of PPAR γ , superfamily of PPAR nuclear receptors (PPAR α,β and γ ), but also insulin sensitive agent lowing blood sugar in clinical practice. Studies have shown that PPAR α,β and γ are playing more and more important roles in cardiovascular diseases and have the hope to become drug targets against I/R injury. In our present study, the effect of treatment with pioglitazone intravenously on rathearts with the model of I/R in vivo was observed and probed related mechanisms.In addition, pivanampeta is a compound with new structure synthesized by Institue of Pharmacology and Toxicology, Academy of Military Medical Science. Previous studies indicate that pivanampeta may protect heart from ischemia and I/R injury induced by isoproteronol and on isolated working heart, improve mitochondrial function of oxidative phosphorylation after hypoxia injury. Moreover, pivanampeta is safe and may be a promising drug against I/R injury. However, the effect of pivanampeta on I/R injury in vivo on rat hearts remains far unknown. Meanwhile, preexperimental results shew that pivanampeta may exsert influence on PPAR Y ?Our present study come to the following results: I. Effects of pioglitazone on rat heart with the model of I/R in vivo1. Effects of pioglitazone on myocardial I/R injury: In pioglitazone-treated group, HR, +dp/dtmax representing the systolic function of heart as well as -dp/dtmax, the indicator of diastolic function, improved dramaticly at lmin and 30min after reperfusion, respectively. Meanwhile MI size was decreased markedly.2. Molecular mechanisms of pioglitazone against myocardial I/R injury: In the model of ischemia 30 min followed by 120min reperfusion, pioglitazone 0.3mg.kg"', lmg.kg'1 and 3mg.kg"' treated hearts reduced apoptotic cardiomyocytes in a dose dependent manner as evidenced by TUNEL. What is more, pioglitazone could also reduce necrosis of cardiac cell as indicated by smear. Pioglitazone might make the fall of Bax and caspase-3, protein promoting cardiomyocyte apoptosis, and increased Bcl-2, protein inhibiting apoptosis.II. The mediation effects of pioglitazone on the expression of PPAR Y and MMP-2, downstream of PPAR y , and the comparison with pivanampeta.1. Effects of pioglitazone on expression of PPARy : Treatment with pioglitazone OJmg.kg"1, lmg.kg"1 and Smg.kg"1 acutely, expression of protein and mRNA of PPAR y were increased concentration-dependently.2. Effects of pioglitazone on expression of MMP-2: In the model of 30 min ischemia followed by 120min reperfusion, dose-dependently pioglitazone 0.3mg.kg"', lmg.kg" and Smg.kg"1 decreased the expression of MMP-2 at protein and mRNA level.3. Effects of pivanampeta on expression of PPAR y : Treatment with pivanampeta 3mg.kg"', 6mg.kg"' and 9mg.kg'1, expression of protein and mRNA of PPAR y were increased concentration-dependently.4. Effects of pivanampeta on expression of MMP-2: In the model of 30 min ischemia followed by 120min reperfusion, dose-dependently pivanampeta 3mg.kg"', 6mg.kg"' and 9mg.kg"' decreased the expression of MMP-2 at protein and mRNA level.5. Effects of pioglitazone on PPARy and MMP-2 comparing with pivanampeta:?Effects of pioglitazone and pivanampeta on PPAR y protein and mRNA: They might activate PPAR y in the similar manner. Before activated, PPAR Y protein existed in cytoplasm, while it mainly located in myocardial nuclei after activated. As for PPAR y mRNA, there is no change in express position but the variation in content only.?Effects of pioglitazone and pivanampeta on MMP-2 protein and mRNA within cardiomyocytes: Both pioglitazone and pivanampeta might reduce MMP-2 protein and mRNA of myocardiac cells markedly. However, there was no significant difference in expression of MMP-2 at the level of protein and mRNA between the two drugs.Thus it can be seen that pivanampeta and pioglitazone may active PPAR y much alike and then to protect hearts from I/R injury, m. Effects of pivanampeta in rat heart with the model of I/R injury in...
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