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(American Journal of Pathology. 2005;166:653-662.)
© 2005 American Society for Investigative Pathology

Elevated Endothelial Nitric Oxide Bioactivity and Resistance to Angiotensin-Dependent Hypertension in 12/15-Lipoxygenase Knockout Mice

Peter B. Anning^*, Barbara Coles^*, Alexandra Bermudez-Fajardo^*, Patricia E.M. Martin^*, Bruce S. Levison, Stanley L. Hazen, Colin D. Funk, Hartmut Kühn and Valerie B. O’Donnell^*

From the Department of Medical Biochemistry and Immunology,^* University of Wales College of Medicine, Cardiff, United Kingdom; the Department of Cell Biology, Cleveland Clinic Foundation, Cleveland, Ohio; the Center for Experimental Therapeutics and Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania; and the Department of Biochemistry, Humboldt University, Berlin, Germany

12/15-Lipoxygenase (12/15-LOX) plays a pathogenic role in atherosclerosis. To characterize whether 12/15-LOX also contributes to endothelial dysfunction and hypertension, regulation of vessel tone and angiotensin II (ang II) responses were characterized in mice deficient in 12/15-LOX. There was a twofold increase in the magnitude of L-nitroarginine-methyl ester-inhibitable, acetylcholine-dependent relaxation or phenylephrine-dependent constriction in aortic rings isolated from 12/15-LOX^–/– mice. Plasma NO metabolites and aortic endothelial NO synthase (eNOS) expression were also elevated twofold. Angiotensin II failed to vasoconstrict 12/15-LOX^–/– aortic rings in the absence of L-nitroarginine-methyl ester, and ang II impaired acetylcholine-induced relaxation in wild-type, but not 12/15-LOX^–/– rings. In vivo, 12/15-LOX^–/– mice had similar basal systolic blood pressure measurements to wild type, however, blood pressure elevations in response to ang II infusion (1.1 mg/kg/day) were significantly attenuated (maximal pressure, 143.4 ± 4 mmHg versus 122.1 ± 5.3 mmHg for wild type and 12/15-LOX^–/–, respectively). In contrast, vascular hypertrophic responses to ang II, and ang II type 1 receptor (AT1-R) expression were similar in both strains. This study shows that 12/15-LOX^–/– mice have increased NO biosynthesis and impaired ang II-dependent vascular responses in vitro and in vivo, suggesting that 12/15-LOX signaling contributes to impaired NO bioactivity in vascular disease in vivo.

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