Oxygen free radical release in human failing myocardium is associated with increased activity of Rac1-GTPase and represents a target for statin treatment
Oxygen free radical release in human failing myocardium is associated with increased activity of Rac1-GTPase and represents a target for statin treatment
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DOI：
10.1161/01.cir.0000091084.46500.bb
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发表时间：
2003-09-30
期刊：
影响因子：
37.8
通讯作者：
Laufs, U
中科院分区：
文献类型：
--
作者：
Maack, C;Kartes, T;Laufs, U
背景-活性氧（ROS）有助于心力衰竭的发展。心肌ROS的一个潜在来源是NADPH氧化酶，它由小的gtp结合蛋白rac1调节。他汀类药物可以抑制rac1的异戊二烯化。因此，我们检测了人衰竭心肌中的ROS和rac1，并在体内测试了他汀类药物对它们的调节作用。方法与结果：在缺血性心肌病（ICM）或扩张型心肌病（DCM）患者左心室心肌中，NADPH氧化酶活性比正常对照组增加1.5倍（P < 0.05, n = 8）。在衰竭心肌中，通过脂质过氧化和乌头酸酶活性测定的氧化应激增加与rac1从细胞质溶胶到膜的易位增加有关。下拉试验显示，ICM和DCM的rac1-GTPase活性增加了3倍。同时，与非衰竭心肌相比，衰竭心肌中NADPH氧化酶亚基p47（phox）而非p67（phox）的膜表达上调。在接受心脏手术的患者中，前瞻性给予阿托伐他汀或普伐他汀（40 mg/d， 4周）治疗的右心房心肌中，与未给予他汀治疗的患者相比，rac1-GTPase活性分别降低至67.9 +/- 12%和65.6 +/- 13.8% （P < 0.05, n = 8）。阿托伐他汀和普伐他汀都能显著降低血管紧张素ii刺激的NADPH氧化酶活性，但不能降低基础的NADPH氧化酶活性。结论：DCM和ICM患者心肌衰竭的特点是NADPH氧化酶介导的ROS释放上调，与rac1活性增加有关。口服他汀类药物可抑制心肌rac1-GTPase活性。这些数据表明，他汀类药物可以在人类中观察到肝外作用，并可能对慢性心力衰竭患者有益。
Background - Reactive oxygen species (ROS) contribute to the development of heart failure. A potential source of myocardial ROS is the NADPH oxidase, which is regulated by the small GTP-binding protein rac1. Isoprenylation of rac1 can be inhibited by statin therapy. Thus, we examined ROS and rac1 in human failing myocardium and tested their regulation by statins in vivo.Methods and Results - In human left ventricular myocardium from patients with ischemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM), NADPH oxidase activity was increased 1.5-fold compared with nonfailing controls (P < 0.05, n = 8). In failing myocardium, increased oxidative stress determined by measurements of lipid peroxidation and aconitase activity was associated with increased translocation of rac1 from the cytosol to the membrane. Pull-down assays revealed a 3-fold increase of rac1-GTPase activity in ICM and DCM. In parallel, membrane expression of the NADPH oxidase subunit p47(phox), but not p67(phox), was upregulated in failing compared with nonfailing myocardium. In right atrial myocardium from patients undergoing cardiac surgery who were prospectively treated with atorvastatin or pravastatin (40 mg/d, 4 weeks), rac1-GTPase activity was decreased to 67.9 +/- 12% and 65.6 +/- 13.8% compared with patients without statin ( P < 0.05, n = 8). Both atorvastatin and pravastatin significantly reduced angiotensin II-stimulated but not basal NADPH oxidase activity.Conclusions - Failing myocardium of patients with DCM and ICM is characterized by upregulation of NADPH oxidase - mediated ROS release associated with increased rac1 activity. Oral statin treatment inhibits myocardial rac1-GTPase activity. These data suggest that extrahepatic effects of statins can be observed in humans and may be beneficial for patients with chronic heart failure.