Circulation. 2002;106:57-62
Published online before print June 17, 2002, doi: 10.1161/01.CIR.0000020682.73694.AB
Published online before print June 17, 2002, doi: 10.1161/01.CIR.0000020682.73694.AB
(Circulation. 2002;106:57.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
Rho-Kinase Mediates Hypoxia-Induced Downregulation of Endothelial Nitric Oxide Synthase
From the Vascular Medicine Research Unit (M.T., J.S., J.K.L.), Brigham and Women’s Hospital and Harvard Medical School, Cambridge, Mass, and the Department of Cardiovascular Medicine (J.H., H.S.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Correspondence to James K. Liao, MD, Vascular Medicine Research Unit, Brigham and Women’s Hospital, 65 Landsdowne St, Room 275, Cambridge, MA 02139. E-mail jliao{at}rics.bwh.harvard.edu
Background— Hypoxia-induced pulmonary hypertension is a major cause of morbidity and mortality. Hypoxia induces pulmonary vasoconstriction, in part, by decreasing endothelial nitric oxide synthase (eNOS) expression. The mechanism by which hypoxia decreases eNOS expression is not known but may involve Rho-kinase–induced actin cytoskeletal changes in vascular endothelial cells.
Methods and Results— To determine whether hypoxia regulates eNOS expression through Rho-kinase, we exposed human saphenous and pulmonary artery endothelial cells to hypoxia (3% O2) with and without a Rho-kinase inhibitor, hydroxyfasudil (0.1 to 100 µmol/L), for various durations (0 to 48 hours). Hypoxia increased Rho-kinase expression and activity by 50% and 74%, decreased eNOS mRNA and protein expression by 66±3% and 57±5%, and inhibited eNOS activity by 48±9%. All of these effects of hypoxia on eNOS were reversed by cotreatment with hydroxyfasudil. Furthermore, inhibition of Rho by Clostridium botulinum C3 transferase or Rho-kinase by overexpression of dominant-negative Rho-kinase reversed hypoxia-induced decrease in eNOS expression. Indeed, disruption of the actin cytoskeleton, the downstream target of Rho-kinase, by cytochalasin D also upregulated eNOS expression. Hypoxia reduced eNOS mRNA half-life from 22±2 to 13±2 hours, which was reversed by cotreatment with hydroxyfasudil. However, neither hypoxia nor hydroxyfasudil had any effects on eNOS gene transcription.
Conclusions— These results indicate that hypoxia-induced decrease in eNOS expression is mediated by Rho-kinase and suggest that Rho-kinase inhibitors may have therapeutic benefits in patients with hypoxia-induced pulmonary hypertension.
Key Words: endothelium • hypoxia • hypertension • nitric oxide
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