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(Hypertension. 2008;51:246.)
© 2008 American Heart Association, Inc.

Original Articles

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; 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.

Correspondence to William B. Campbell, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail wbcamp{at}mcw.edu

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 β-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 β-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 β-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 β-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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