期刊
CIRCULATION RESEARCH
卷 99, 期 12, 页码 1426-1432出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000251668.39526.c7
关键词
atherosclerosis; endothelium; nitric oxide; Rho kinase; vasodilation
资金
- NHLBI NIH HHS [R01 HL070274-05, P01 HL-48743, R01 HL070274, R01 HL080187, R01 HL052233-11, P01 HL048743, R01 HL052233-12, R01 HL080187-03, R01 HL052233, HL52233, R01 HL080187-02, R01 HL070274-04] Funding Source: Medline
- NIDDK NIH HHS [R01 DK062729, R01 DK062729-05, R01 DK062729-04] Funding Source: Medline
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 9.4 +/- 1.9% to 13.4 +/- 1.9% (P = 0.001) but not in healthy controls (from 11.3 +/- 1.4% to 7.7 +/- 1.1%; P = 0.07). Endothelium-independent vasodilation was not affected by fasudil in either CAD or healthy subjects. Fasudil reduced Rho kinase activity by 59 +/- 18% in CAD subjects (P = 0.001) but not in healthy subjects (by 3 +/- 6%; P = 0.60). 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) (r = -0.48; P = 0.01). 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.
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