TY - JOUR
T1 - Elevated endothelial nitric oxide bioactivity and resistance to angiotensin-dependent hypertension in 12/15-lipoxygenase knockout mice
AU - Anning, Peter B.
AU - Coles, Barbara
AU - Bermudez-Fajardo, Alexandra
AU - Martin, Patricia E.M.
AU - Levison, Bruce S.
AU - Hazen, Stanley L.
AU - Funk, Colin D.
AU - Kühn, Hartmut
AU - O'Donnell, Valerie B.
N1 - Funding Information:
Supported by the Wellcome Trust (V.B.O. and P.B.A.), the British Heart Foundation (V.B.O.), the Deutsche Forschungsgemeinschaft (Ku961-8-1 to H.K.), and the National Institutes of Health (grants HL53558 to C.D.F., HL61878 and HL62526 to S.L.H. ).
PY - 2005/3
Y1 - 2005/3
N2 - 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.
AB - 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.
U2 - 10.1016/S0002-9440(10)62287-0
DO - 10.1016/S0002-9440(10)62287-0
M3 - Article
C2 - 15743778
AN - SCOPUS:14644426612
SN - 0002-9440
VL - 166
SP - 653
EP - 662
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 3
ER -