Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
Mol Cell Biochem. 2004 Aug;263(1):179-88. doi: 10.1023/B:MCBI.0000041860.97991.7a.
Angiotensin II (AngII) type 1 receptor (AT1R) blockers (ARBs) limit left ventricular (LV) dysfunction and necrosis after reperfused myocardial infarction (RMI) and proteomics can detect changes in protein levels after injury. We applied proteomics to detect changes in levels of specific protein in the ischemic zone (IZ) and non-ischemic zone (NIZ) of dog hearts after in vivo RMI (90 min of anterior ischemia; 120 min of reperfusion) and treatment with intravenous vehicle (control) and the ARBs valsartan or irbesartan (10 mg/kg) over 30 min before RMI. We also assessed LV function, infarction and apoptosis. Both ARBs limited the RMI-induced LV dysfunction, infarct size and apoptosis. Proteomics detected differential expression of 5 randomly selected proteins in the IZ compared to the NIZ after RMI: decrease in α subunit of ATP synthase isoform precursor (consistent with increased conversion to α subunit under metabolic stress), M chain creatine kinase (consistent with cellular damage) and ventricular myosin light chain-1 (consistent with structural damage and decreased contractility); and increase in NAD(+)-isocitrate dehydrogenase (ICDH) and α subunit and ATP synthase D chain (mitochondrial, consistent with metabolic dysfunction). Importantly, changes in NAD+-ICDH and ATP synthase D chain were reversed by ARB therapy. Thus, proteomics can detect regional changes in metabolic, contractile, and structural proteins after RMI and several of these proteins are favorably modified by ARBs, suggesting that they may be novel therapeutic targets. (Mol Cell Biochem 263: 179-188, 2004).
血管紧张素 II（AngII）型 1 受体（AT1R）阻滞剂（ARB）可限制再灌注心肌梗死（RMI）后左心室（LV）功能障碍和坏死，蛋白质组学可检测到损伤后蛋白质水平的变化。我们应用蛋白质组学检测了犬心肌体内 RMI（前缺血 90 分钟；再灌注 120 分钟）后缺血区（IZ）和非缺血区（NIZ）特定蛋白水平的变化，以及静脉注射载体（对照）和 ARB 缬沙坦或厄贝沙坦（10mg/kg）在 RMI 前 30 分钟治疗的变化。我们还评估了 LV 功能、梗死和细胞凋亡。两种 ARB 均限制了 RMI 诱导的 LV 功能障碍、梗死面积和细胞凋亡。蛋白质组学检测到 RMI 后 IZ 与 NIZ 相比，有 5 种随机选择的蛋白质差异表达：ATP 合酶同工型前体的α亚基减少（与代谢应激下向α亚基的转化一致），肌酸激酶 M 链（与细胞损伤一致）和心室肌球蛋白轻链-1（与结构损伤和收缩力下降一致）；NAD（+）-异柠檬酸脱氢酶（ICDH）和 ATP 合酶 D 链增加（线粒体，与代谢功能障碍一致）。重要的是，ARB 治疗可逆转 NAD+-ICDH 和 ATP 合酶 D 链的变化。因此，蛋白质组学可以检测 RMI 后代谢、收缩和结构蛋白的区域性变化，ARB 对其中几种蛋白进行了有利的修饰，提示它们可能是新的治疗靶点。（Mol Cell Biochem 263: 179-188, 2004）。
