Oxygen Free Radical Release in Human Failing Myocardium Is Associated With Increased Activity of Rac1-GTPase and Represents a Target for Statin Treatment

Abstract

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 (PϽ0.05, nϭ8). 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 67.9Ϯ12% and 65.6Ϯ13.8% compared with patients without statin (PϽ0.05, nϭ8). 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. (Circulation. 2003;108:1567-1574.)

NADPH oxidase-derived reactive oxygen species in cardiac pathophysiology

“…An increased cardiac expression of the NADPH oxidase subunits, NOX2 and p22 phox , was also reported after myocardial infarction both in an animal model (Fukui et al 2001) and in human myocardium (Krijnen et al 2003). Recently, our group and others confirmed that myocardium from end-stage human CHF patients demonstrates increased NADPH oxidase activity (Heymes et al 2003;Maack et al 2003).…”

Spectrum of Pleiotropic Effects of Statins in Heart Failure

“…Insofar as statins inhibit isoprenylation of Rac1, these drugs also decrease the production of ROS. [11] Indeed, in rat models of heart failure treatment with statins was associated with decreased progression to heart failure after aortic banding. Importantly, simvastatin treated rats displayed lower tissue levels of superoxide anion production.…”

Protective Effect of Potassium Against the Hypertensive Cardiac Dysfunction

“…NADPH oxidase has been reported to possess a pivotal role as ROS origin in the failing myocardium of the patients with dilated or ischemic cardiomyopathy and the myocardium of the pressure-overloaded guinea pig. 25,26 Excess ROS, possibly from NADPH oxidase, can inhibit sarcoplasmic reticulum Ca 2ϩ uptake pump by irreversible direct oxidation of its thiol residue 27 or by impairment of the physiological phosphorylation of phospholamban. 28 The dual effects of ROS on intracellular Ca 2ϩ concentration might be involved in the mechanisms for ROS-induced cardiac dysfunction.…”