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(Circulation Research. 2006;98:962.)
© 2006 American Heart Association, Inc.

Integrative Physiology

Endothelial Dysfunction and Hypertension in Rats Transduced With CYP4A2 Adenovirus

Ji-Shi Wang^*, Harpreet Singh^*, Frank Zhang, Tsuneo Ishizuka, Huan Deng, Rowena Kemp, Michael S. Wolin, Thomas H. Hintze, Nader G. Abraham, Alberto Nasjletti, Michal Laniado-Schwartzman

From the Departments of Pharmacology and Physiology, New York Medical College, Valhalla, New York.

Correspondence to Michal Laniado-Schwartzman, PhD, Department of Pharmacology, New York Medical College, Valhalla, NY 10595. E-mail michal_Schwartzman{at}nymc.edu

Vascular cytochrome P450 (CYP) 4A enzymes catalyze the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE), an eicosanoid which participates in the regulation of vascular tone by sensitizing the smooth muscle cells to constrictor and myogenic stimuli. This study was undertaken to investigate the consequences of CYP4A overexpression on blood pressure and endothelial function in rats treated with adenoviral vectors carrying the CYP4A2 construct. Intravenous injection of Adv-CYP4A2 increased blood pressure (from 114±1 to 133±1 mm Hg, P<0.001), and interlobar renal arteries from these rats displayed decreased relaxing responsiveness to acetylcholine, which was offset by treatment with an inhibitor of CYP4A. Relative to data in control rats, arteries from Adv-CYP4A2–transduced rats produced more 20-HETE (129±10 versus 97±7 pmol/mg protein, P<0.01) and less nitric oxide (NO; 4.2±1.6 versus 8.4±1 nmol nitrite+nitrate/mg; P<0.05). They also displayed higher levels of oxidative stress as measured by increased generation of superoxide anion and increased expression of nitrotyrosine and gp91phox. Collectively, these findings demonstrate that augmentation in vascular 20-HETE promotes the development of hypertension and causes endothelial dysfunction, a condition characterized by decreased NO synthesis and/or bioavailability, imbalance in the relative contribution of endothelium-derived relaxing and contracting factors, and enhanced endothelial activation.

Key Words: arachidonic acid • 20-HETE • nitric oxide • eNOS • superoxide anion

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