Role of p90 ribosomal S6 kinase-mediated prorenin-converting enzyme in ischemic and diabetic myocardium
Role of p90 ribosomal S6 kinase-mediated prorenin-converting enzyme in ischemic and diabetic myocardium
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DOI：
10.1161/circulationaha.105.578278
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发表时间：
2006-04-11
期刊：
影响因子：
37.8
通讯作者：
Abe, J
中科院分区：
文献类型：
--
作者：
Itoh, S;Ding, B;Abe, J
背景-流行病学数据强烈表明糖尿病增加心力衰竭的发生率。虽然心肌梗死期间和之后血管紧张素转换酶抑制剂（ACE-I）治疗的益处在糖尿病患者中比非糖尿病患者更大，并且涉及到肾素-血管紧张素系统（RAS）的激活，这些作用的分子基础仍不清楚。方法和结果-我们产生了心脏特异性过表达野生型p90核糖体S6激酶的转基因小鼠（WT-p90 RSK-Tg）和显性负性形式的p90 RSK（DN-p90 RSK-Tg）。在WT-p90 RSK-Tg分离的小鼠心脏中，缺血/再灌注后心脏功能的恢复显著受损。基质辅助激光解吸/电离飞行时间质谱法显示特异性诱导WT-p90 RSK-Tg小鼠中的前肾素转换酶（PRICE）。在WT-p90 RSK-Tg小鼠中，灌注后血管紧张素原蛋白连续减少证实了PRICE的mRNA诱导，表明WT-p90 RSK-Tg小鼠中血管紧张素原切割和随后的RAS激活增加。我们研究了RAS在WT-p90 RSK-Tg动物缺血/再灌注后使用ACE-I（卡托普利）和血管紧张素II 1型受体阻滞剂（奥美沙坦）的作用。我们在非Tg同窝对照中未观察到这些抑制剂的任何作用，因此证实了啮齿动物中的其他报告。相反，在WT-p90 RSK-Tg小鼠中，卡托普利和奥美沙坦均显著改善心脏功能并减小梗死面积。在8个月大时，WT-p90 RSK-Tg小鼠出现心功能障碍。p90 RSK活性和PRICE mRNA都增加了链脲霉素诱导的高血糖症在非Tg同窝对照，而DN-p90 RSK-Tg动物暴露于链脲霉素没有PRICE induction. Conclusions-这项研究表明，在高血糖症介导的心肌PRICE诱导的p90 RSK的关键作用，这可能解释了糖尿病心脏中RAS的增强，并提供了治疗糖尿病心肌病的替代治疗方法。
Background-Epidemiological data strongly indicate that diabetes increases the incidence of heart failure. Although the benefit of angiotensin-converting enzyme inhibitor (ACE-I) treatment during and after myocardial infarction has been found to be greater in diabetics than nondiabetics and activation of the renin-angiotensin system (RAS) has been implicated, the molecular basis of these actions remains unclear.Methods and Results-We generated transgenic mice with cardiac-specific overexpression of wild-type p90 ribosomal S6 kinase (WT-p90RSK-Tg) and a dominant-negative form of p90RSK (DN-p90RSK-Tg). Recovery of cardiac function after ischemia/reperfusion in WT-p90RSK-Tg isolated mouse hearts was significantly impaired. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry revealed specific induction of prorenin-converting enzyme (PRECE) in WT-p90RSK-Tg mice. mRNA induction of PRECE was confirmed with serial angiotensinogen protein reduction after perfusion in WT-p90RSK-Tg mice, suggesting an increase of angiotensinogen cleavage and subsequent RAS activation in WT-p90RSK-Tg mice. We investigated the role of the RAS in WT-p90RSK-Tg animals after ischemia/reperfusion with the use of an ACE-I (captopril) and an angiotensin II type 1 receptor blocker (olmesartan). We did not observe any effect of these inhibitors in non-Tg littermate controls, thus corroborating other reports in rodents. In contrast, both captopril and olmesartan significantly improved cardiac function and reduced infarct size in WT-p90RSK-Tg mice. At 8 months of age, WT-p90RSK-Tg mice developed cardiac dysfunction. p90RSK activity and PRECE mRNA were both increased by streptozotocin-induced hyperglycemia in non-Tg littermate controls, whereas DN-p90RSK-Tg animals exposed to streptozotocin did not have PRECE induction.Conclusions-This study demonstrates the critical role of p90RSK in hyperglycemia-mediated myocardial PRECE induction, which may explain the augmentation of the RAS in diabetic hearts and provide an alternative therapeutic approach to treat diabetic cardiomyopathy.