title: Protective effect of urantide against ischemia-reperfusion injury via protein kinase C and phosphtidylinositol 3'-kinase - Akt pathway.
abstract: Urantide is the most potent UT receptor antagonist compound found to date. Our previous studies have shown that it has cardioprotective effect against ischemia-reperfusion injury. However, it is unclear which signal transduction pathways are involved in the urantide-induced cardioprotective effect. This study was designed to investigate whether the effect of urantide on myocardial ischemia-reperfusion injury in rats via the protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway. The results showed that urantide at 10 and 30 µg/kg markedly inhibited the increases in serum creatine kinase fraction and lactate dehydrogenase activities and the level of cardiac troponin I, reduced the ratio of myocardial infarct size to area at risk. Urantide significantly decreased the histological damage to the myocardium and modified the ultrastructural damage in cardiac myocytes. In the presence of chelerythrine (an inhibitor of PKC, 1 mg/kg) or LY294002 (an inhibitor of PI3K-Akt, 0.3 mg/kg), the protective effect of urantide was almost completely abolished. Urantide (30 µg/kg) markedly enhanced the expression of p-Akt protein during myocardial ischemia-reperfusion injury, and this enhancement was significantly attenuated by LY294002. Therefore, our results demonstrate that urantide has a potent protective effect against myocardial ischemia-reperfusion injury in rats that may be involved with the PKC and PI3K-Akt signaling pathways.
authors.affiliation: Department of Pharmacology, Anhui Medical University, Hefei, PR China.
authors.forename: Jun-Yan
authors.initials: JY
authors.lastname: Zhang
authors.forename: Zhi-Wu
authors.initials: ZW
authors.lastname: Chen
authors.forename: Hua
authors.initials: H
authors.lastname: Yao
mesh_terms: D000818:Animals; D053119:Benzophenanthridines / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D003402:Creatine Kinase / Q000097:blood; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D019210:Troponin I / Q000097:blood; D014579:Urotensins / Q000494:pharmacology*
chemical_list: D053119:Benzophenanthridines; D002316:Cardiotonic Agents; D002867:Chromones; D003402:Creatine Kinase; D007770:L-Lactate Dehydrogenase; D009025:Morpholines; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D051057:Proto-Oncogene Proteins c-akt; D019210:Troponin I; D014579:Urotensins; C492079:urotensin II (4-11), Pen(5)-Trp(7)-Orn(8)-; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C016299:chelerythrine