Published Online
on January 7, 2008

A more recent version of this article appeared on February 1, 2008

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Submitted on October 30, 2007
Revised on November 15, 2007

Endothelial 15-Lipoxygenase-1 Overexpression Increases Acetylcholine-Induced Hypotension and Vasorelaxation in Rabbits

Nitin T. Aggarwal; Yuttanna Chawengsub; Kathryn M. Gauthier; Helena Viita; Seppo Yla-Herttuala; and William B. Campbell^*

From the Department of Pharmacology and Toxicology (N.T.A., Y.C., K.M.G., W.B.C.), Medical College of Wisconsin, Milwaukee; and the Department of Biotechnology and Molecular Medicine (H.V., S.Y-H.), A I Virtanen Institute of Molecular Science, University of Kuopio, Kuopio, Finland.

^* To whom correspondence should be addressed. E-mail: wbcamp{at}mcw.edu.

Abstract—Arachidonic acid is metabolized by the 15-lipoxygenase-1 pathway to the vasodilatory eicosanoids hydroxy-epoxyeicosatrienoic acid and trihydroxyeicosatrienoic acid. We determined the in vitro and in vivo effects of the 15-lipoxygenase-1 metabolites in rabbits infected with adenovirus containing cDNA for human 15-lipoxygenase-1 (Ad-15-LO-1). Forty hours after intravenous adenoviral injection, 15-lipoxygenase-1 expression increased in liver and mesenteric arteries 10-fold and 3-fold, respectively. Expression of 15-LO-1 was limited to the endothelium of mesenteric arteries. Overexpression did not occur in tissues from rabbits infected with a -galactosidase containing adenovirus. Trihydroxyeicosatrienoic acid and hydroxy-epoxyeicosatrienoic acid synthesis per milligram of tissue increased by 2.1- and 1.5-fold, respectively, in mesenteric arteries from Ad-15-LO-1–infected rabbits compared with normal rabbits. Pretreatment with a 15-lipoxygenase inhibitor BW755C inhibited the synthesis. NO and prostaglandin-independent, maximal relaxations to acetylcholine were greater in mesenteric arteries from Ad-15-LO-1–infected rabbits (98.3±1.7%) compared with normal (60.93±10.5%) and -galactosidase containing adenovirus–infected rabbits (68.3±7.7%). Pretreatment with BW755C decreased these relaxations. Mean arterial pressure and heart rate did not differ in Ad-15-LO-1–infected rabbits compared with normal or -galactosidase containing adenovirus–infected rabbits. The hypotensive responses to acetylcholine in the presence and absence of inhibition of NO and prostaglandins were greater in Ad-15-LO-1–infected rabbits (-52±2% and -47±2%) compared with normal (-31±3% and -25±5%) or -galactosidase containing adenovirus–infected rabbits (-38±2% and -30±3%). Therefore, increased expression of 15-LO-1 increases acetylcholine relaxation in arteries and hypotensive responses in rabbits because of increased hydroxy-epoxyeicosatrienoic acid and trihydroxyeicosatrienoic acid synthesis.

Key words: endothelium-derived hyperpolarizing factors • endothelium • adenovirus • hypotension • mean arterial pressure

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