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

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 51; no. 2; pp. 246 - 251
• Main Authors: Aggarwal, Nitin T, Chawengsub, Yuttanna, Gauthier, Kathryn M, Viita, Helena, Yla-Herttuala, Seppo, Campbell, William B
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.02.2008; Hagerstown, MD Lippincott
• Subjects: Acetylcholine; Adenovirus; Animals; Arachidonate 15-Lipoxygenase - genetics; Arachidonate 15-Lipoxygenase - metabolism; Arachidonic Acid - metabolism; Arterial hypertension. Arterial hypotension; Arteries - enzymology; Arteries - physiopathology; Biological and medical sciences; Blood and lymphatic vessels; Blotting, Western; Cardiology. Vascular system; Endothelium, Vascular - enzymology; Experimental diseases; Gene Transfer Techniques; Hemodynamics; Humans; Hypotension - chemically induced; Hypotension - physiopathology; Immunohistochemistry; In Vitro Techniques; Isoenzymes - genetics; Isoenzymes - metabolism; Isometric Contraction; Liver - blood supply; Medical sciences; Mesenteric Arteries - physiopathology; Rabbits; Up-Regulation; Vasodilation; Vasodilator Agents; Hypertension; hypotension; Enzyme; mean arterial pressure; Rabbit; endothelium-derived hyperpolarizing factors; Cardiovascular disease; Lagomorpha; Endothelium; Vertebrata; Mammalia; Animal; adenovirus; Neurotransmitter; Arterial pressure; Acetylcholine; Oxidoreductases; Lipoxygenase
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.107.104125

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.