Strande Jennifer L, Hsu Anna, Su Jidong, Fu Xiangping, Gross Garrett J, Baker John E
Division of Cardiovascular Medicine, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA.
Basic Res Cardiol. 2007 Jul;102(4):350-8. doi: 10.1007/s00395-007-0653-4. Epub 2007 Apr 30.
Myocardial ischemia/reperfusion (I/R) injury is partly mediated by thrombin. In support, the functional inhibition of thrombin has been shown to decrease infarct size after I/R. Several cellular responses to thrombin are mediated by a G-protein coupled protease-activated receptor 1 (PAR1).However, the role of PAR1 in myocardial I/R injury has not been well characterized. Therefore, we hypothesized that PAR1 inhibition will reduce the amount of myocardial I/R injury. After we detected the presence of PAR1 mRNA and protein in the rat heart by RT-PCR and immunoblot analysis,we assessed the potential protective role of SCH 79797, a selective PAR1 antagonist, in two rat models of myocardial I/R injury. SCH 79797 treatment immediately before or during ischemia reduced myocardial necrosis following I/R in the intact rat heart. This response was dose-dependent with the optimal dose being 25 microg/kg IV. Likewise, SCH 79797 treatment before ischemia in the isolated heart model reduced infarct size and increased ventricular recovery following I/R in the isolated heart model with an optimal concentration of 1 microM. This reduction was abolished by a PAR1 selective agonist. SCH 79797-induced resistance to myocardial ischemia was abolished by wortmannin, an inhibitor of PI3 kinase; L-NMA, a NOS inhibitor; and glibenclamide, a nonselective K(ATP) channel blocker. PAR1 activating peptide,wortmannin, L-NMA and glibenclamide alone had no effect on functional recovery or infarct size. A single treatment of SCH 79797 administered prior to or during ischemia confers immediate cardioprotection suggesting a potential therapeutic role of PAR1 antagonist in the treatment of injury resulting from myocardial ischemia and reperfusion.
心肌缺血/再灌注（I/R）损伤部分是由凝血酶介导的。作为证据，凝血酶的功能抑制已被证明可减小I/R后的梗死面积。凝血酶的几种细胞反应是由G蛋白偶联蛋白酶激活受体1（PAR1）介导的。然而，PAR1在心肌I/R损伤中的作用尚未得到充分阐明。因此，我们推测抑制PAR1将减少心肌I/R损伤的程度。通过逆转录聚合酶链反应（RT-PCR）和免疫印迹分析检测到PAR1信使核糖核酸（mRNA）和蛋白质在大鼠心脏中的存在后，我们评估了选择性PAR1拮抗剂SCH 79797在两种大鼠心肌I/R损伤模型中的潜在保护作用。在完整大鼠心脏中，在缺血前或缺血期间立即给予SCH 79797治疗可减少I/R后的心肌坏死。这种反应呈剂量依赖性，最佳剂量为静脉注射25微克/千克。同样，在离体心脏模型中，缺血前给予SCH 79797治疗可减少梗死面积，并增加离体心脏模型I/R后的心室恢复，最佳浓度为1微摩尔。PAR1选择性激动剂可消除这种减少。PI3激酶抑制剂渥曼青霉素、一氧化氮合酶（NOS）抑制剂L-NMA和非选择性钾离子ATP（K(ATP)）通道阻滞剂格列本脲可消除SCH 79797诱导的对心肌缺血的抵抗作用。单独使用PAR1激活肽、渥曼青霉素、L-NMA和格列本脲对功能恢复或梗死面积没有影响。在缺血前或缺血期间单次给予SCH 79797可立即提供心脏保护作用，这表明PAR1拮抗剂在治疗心肌缺血和再灌注导致的损伤方面具有潜在的治疗作用。
