Abstract-Investigations from basic biology suggest that activation of the Rho/Rho kinase pathway reduces the bioavailability of nitric oxide (NO) and thereby promotes atherosclerosis and its clinical complications. Yet, little information is available about the relationship of the Rho/Rho kinase pathway to NO bioavailability in humans with atherosclerosis. Accordingly, we determined whether inhibition of Rho kinase augments NO bioavailability and improves endothelial function in human subjects with coronary artery disease (CAD). Thirteen CAD subjects and 16 age-and sex-matched healthy controls were randomly assigned to receive the Rho kinase inhibitor, fasudil, or placebo for 1 month each in a double-blind crossover trial. Flow-mediated, endothelium-dependent and nitroglycerin-induced, endothelium-independent vasodilation were assessed by brachial artery ultrasonography. Rho kinase activity was measured in peripheral leukocytes. Fasudil increased endothelium-dependent vasodilation in CAD subjects from 9.4Ϯ1.9% to 13.4Ϯ1.9% (Pϭ0.001) but not in healthy controls (from 11.3Ϯ1.4% to 7.7Ϯ1.1%; Pϭ0.07). Endothelium-independent vasodilation was not affected by fasudil in either CAD or healthy subjects. Fasudil reduced Rho kinase activity by 59Ϯ18% in CAD subjects (Pϭ0.001) but not in healthy subjects (by 3Ϯ6%; Pϭ0.60). The change in endothelium-dependent vasodilation achieved with fasudil relative to placebo was inversely proportional to Rho kinase inhibition (ie, greater Rho kinase inhibition was associated with larger improvement in endothelium-dependent vasodilation) (rϭϪ0.48; Pϭ0.01). These findings suggest that Rho/Rho kinase activation promotes endothelial dysfunction in humans with atherosclerosis. Inhibition of the Rho/Rho kinase pathway should provide a useful strategy to restore NO bioavailability in humans with atherosclerosis. , that regulate vascular tone, maintain blood cell/vessel wall interaction, prevent thrombosis, and limit smooth muscle cell proliferation. 1 Reduced NO bioavailability, or endothelial dysfunction, is a hallmark of atherosclerosis and predicts adverse cardiovascular events. 2,3 A more complete understanding of the molecular mechanisms that impair NO bioavailability in humans with atherosclerosis will facilitate better strategies to reduce the progression and the overt clinical manifestations of this disease.The small GTP-binding protein Rho, and its downstream effector, Rho kinase, have been implicated in many of the pathologic processes that underlie atherosclerosis including endothelial dysfunction, vasoconstriction, inflammation, cellular migration and proliferation, and a procoagulant state. 4,5 Basic studies have shown that inhibition of Rho/Rho kinase augments the expression and activity of endothelial nitric oxide synthase (eNOS), 6 -8 whereas overactivity of the Rho/ Rho kinase pathway, as occurs in experimental atherosclerosis, reduces NO bioavailability. 9,10 It is unknown, however, whether the Rho/Rho kinase pathway is overactive in human atherosclerosis and, hence, whether...

Background In addition to inhibiting cholesterol synthesis, statins (HMG-CoA reductase inhibitors) decrease the formation of isoprenoid intermediates required for the activation of key signaling pathways, including Rho/Rho kinase (ROCK). In experimental settings, statins inhibit ROCK and reverse vascular dysfunctions in atherosclerosis, independent of cholesterol reduction. It is not known whether statins inhibit ROCK activity in humans with atherosclerosis. Methods We investigated 35 patients with stable atherosclerosis in a randomized, double-blind study comparing treatment with high-dose (80 mg/d) or low-dose (10 mg/d) atorvastatin to placebo for 28 days. Blood samples for leukocyte ROCK activity, fasting lipids, and high-sensitivity C-reactive protein (hs-CRP) were obtained on days 0, 7, 14, and 28 after randomization and change over time with the 2 statin treatments relative to placebo was examined. Results Atorvastatin 80 mg/d reduced ROCK activity (p=0.002 vs. placebo). This decline was rapid and significant within 2 weeks of treatment. The inhibition of ROCK by atorvastatin (80 mg/d) remained significant even after controlling for changes in low-density lipoprotein cholesterol (LDL-C) and triglycerides (p=0.01). Furthermore, there was no correlation between changes in ROCK activity and changes in LDL-C (r=0.2, p=0.25) or triglycerides (r=0.1, p=0.55). There was a modest correlation between ROCK inhibition and change in hs-CRP among patients randomized to atorvastatin 80 mg/d (r=0.6, p=0.07). Conclusions These first-in-man findings demonstrate that high-dose atorvastatin rapidly inhibits the pro-atherogenic Rho/ROCK pathway, independent of cholesterol reduction. This inhibition may contribute to the clinical benefits of statins. Rho/ROCK may provide a useful therapeutic target in patients with atherosclerosis.

Transdiaphragmatic omental harvest provides safe and efficient coverage of deep sternal wounds without a laparotomy incision.