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Mechanisms mediating the cardioprotective effects of rapamycin in ischaemia–reperfusion injury
Author(s) -
Liu YouBin,
Yu Bo,
Li ShuFeng,
Fan Ying,
Han Wei,
Yu JiangBo,
Wang Zheng,
Li XiangLu,
Sun LiPing,
Yang ShuSen
Publication year - 2011
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2010.05467.x
Subject(s) - cardioprotection , protein kinase b , reperfusion injury , enos , pi3k/akt/mtor pathway , kinase , medicine , ischemia , pharmacology , phosphorylation , nitric oxide , creatine kinase , lactate dehydrogenase , ly294002 , chemistry , endocrinology , nitric oxide synthase , signal transduction , biochemistry , enzyme
Summary 1. In the present study, the temporal and concentration‐dependent cardioprotective effects of rapamycin against ischaemia–reperfusion (I/R) injury, as well as the underlying mechanisms, were investigated. 2. Rat Langendorff‐perfused isolated hearts were exposed to 40 min global ischaemia followed by 120 min reperfusion. Hearts were perfused with different concentrations of rapamycin before and after ischaemia. Myocardial injury was assessed in terms of infarct size and the release of lactate dehydrogenase (LDH) and creatine kinase (CK). The phosphorylation of Akt, extracellular signal‐regulated kinase (ERK) 1/2 and endothelial nitric oxide synthase (eNOS) was determined at the end of reperfusion. 3. When administered prior to ischaemia, 25, 50 and 100 nmol/L rapamycin significantly reduced infarct size compared with control (40.1 ± 1.5, 26.3 ± 4.1 and 21.2 ± 3.4 vs 52.5 ± 4.5%, respectively) without affecting the recovery of ventricular function. No reduction in infarct size was observed when 50 nmol/L rapamycin was administered 10 or 120 min into the reperfusion period. 4. Rapamycin (50 nmol/L) enhanced the phosphorylation of Akt kinase but did not affect the phosphorylation of ERK1/2 or eNOS at the end of reperfusion. The cardioprotective effect of rapamycin was blocked by the phosphatidylinositol 3‐kinase (Akt) inhibitor LY294002 (15 nmol/L). 5. In conclusion, rapamycin mediates cardioprotection prior to ischaemia and after reperfusion. This protection may involve activation of the phosphatidylinositol 3‐kinase pathway.