Endothelial dysfunction and hypertension in rats transduced with CYP4A2 adenovirus.
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.
Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
Ji-Shi
JS
Wang
Harpreet
H
Singh
Frank
F
Zhang
Tsuneo
T
Ishizuka
Huan
H
Deng
Rowena
R
Kemp
Michael S
MS
Wolin
Thomas H
TH
Hintze
Nader G
NG
Abraham
Alberto
A
Nasjletti
Michal
M
Laniado-Schwartzman
D000256:Adenoviridae; D000818:Animals; D001794:Blood Pressure; D019556:COS Cells; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005822:Genetic Vectors; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D006973:Hypertension / Q000201:enzymology*; D009206:Myocardium / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar
D006893:Hydroxyeicosatetraenoic Acids; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; C465388:cytochrome P-450 CYP4A2 (rat)