Sivarajah Ahila, McDonald Michelle C, Thiemermann Christoph
Centre for Experimental Medicine, Nephrology and Critical Care, The William Harvey Research Institute, St. Bartholomew's Queen Mary-University of London, UK.
J Pharmacol Exp Ther. 2005 May;313(2):896-901. doi: 10.1124/jpet.104.080598. Epub 2005 Feb 25.
We investigated whether endogenous ligands of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) protect the heart against ischemia-reperfusion (I/R) injury. The selective PPAR-gamma antagonist GW9662 (2-chloro-5-nitrobenzanilide) was used in rat models of 1) regional myocardial I/R, 2) ischemic preconditioning, and 3) delayed cardioprotection by endotoxin. We also investigated the effects of the selective cyclooxygenase-2 inhibitor, parecoxib, on ischemic preconditioning and delayed cardioprotective effects of endotoxin. Male Wistar rats were anesthetized with sodium thiopentone. Animals were subjected to either 15 or 25 min of regional myocardial I/R and pretreated with the PPAR-gamma agonist ciglitazone (0.3 mg/kg), the PPAR-gamma antagonist GW9662 (1 mg/kg), or GW9662 and ciglitazone. Animals were also subjected to either 1) ischemic preconditioning alone, ischemic preconditioning, and pretreated with either GW9662 or parecoxib (20 mg/kg) or 2) lipopolysaccharide (LPS) (1 mg/kg) alone, LPS, and pretreated with ciglitazone, GW9662, or parecoxib (20 mg/kg). Myocardial infarct size was determined by p-nitroblue tetrazolium staining. The PPAR-gamma antagonist GW9662 (1 mg/kg) abolished the cardioprotection afforded by the potent PPAR-gamma agonist ciglitazone (0.3 mg/kg). Neither GW9662 nor parecoxib affected the cardioprotective effects of ischemic preconditioning. Pretreatment with ciglitazone did not provide additional cardioprotection to LPS-treated animals. Both GW9662 and parecoxib abolished the delayed cardioprotective effects of endotoxin. Thus, we propose that 1) endogenous ligands of PPAR-gamma are being generated by myocardial ischemia in sufficient amounts to attenuate myocardial I/R injury, and 2) that cyclooxygenase-2 metabolites contribute to (or even account for) the cardioprotective effects of endotoxin (second window of protection) by acting as endogenous PPAR-gamma ligands.
我们研究了过氧化物酶体增殖物激活受体γ（PPAR-γ）的内源性配体是否能保护心脏免受缺血再灌注（I/R）损伤。选择性PPAR-γ拮抗剂GW9662（2-氯-5-硝基苯甲酰胺）被用于以下大鼠模型：1）局部心肌I/R，2）缺血预处理，以及3）内毒素诱导的延迟性心脏保护。我们还研究了选择性环氧化酶-2抑制剂帕瑞昔布对内毒素缺血预处理和延迟性心脏保护作用的影响。雄性Wistar大鼠用硫喷妥钠麻醉。动物接受15或25分钟的局部心肌I/R，并分别用PPAR-γ激动剂吡格列酮（0.3mg/kg）、PPAR-γ拮抗剂GW9662（1mg/kg）或GW9662与吡格列酮进行预处理。动物还接受以下处理：1）单独进行缺血预处理，缺血预处理并用GW9662或帕瑞昔布（20mg/kg）预处理，或2）单独使用脂多糖（LPS）（1mg/kg），LPS并用吡格列酮、GW9662或帕瑞昔布（20mg/kg）预处理。通过对硝基蓝四氮唑染色测定心肌梗死面积。PPAR-γ拮抗剂GW9662（1mg/kg）消除了强效PPAR-γ激动剂吡格列酮（0.3mg/kg）提供的心脏保护作用。GW9662和帕瑞昔布均未影响缺血预处理的心脏保护作用。吡格列酮预处理并未为LPS处理的动物提供额外的心脏保护。GW9662和帕瑞昔布均消除了内毒素的延迟性心脏保护作用。因此，我们提出：1）心肌缺血产生的PPAR-γ内源性配体足以减轻心肌I/R损伤；2）环氧化酶-2代谢产物通过作为内源性PPAR-γ配体，对内毒素的心脏保护作用（第二保护窗）有贡献（甚至起作用）。
