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...
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