Oxygen free radical release in human failing myocardium is associated with increased activity of Rac1-GTPase and represents a target for statin treatment

Article

关键词: CARDIAC MYOCYTE HYPERTROPHY;    NADPH OXIDASE ACTIVITY;    A REDUCTASE INHIBITOR;    OXIDATIVE STRESS;    HEART-FAILURE;    RAC1 GTPASE;    CELLS;    ACTIVATION;    MICE;    PROGRESSION;   

DOI  :  10.1161/01.CIR.0000091084.46500.BB

来源: SCIE

【 摘 要 】

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.

【 授权许可】

Free