Cerebral vascular dysfunction mediated by superoxide in hyperhomocysteinemic mice.
OBJECTIVE
Hyperhomocysteinemia is an emerging risk factor for stroke, but little is known about effects of hyperhomocysteinemia on cerebral vascular function. We tested the hypothesis that chronic hyperhomocysteinemia in mice causes endothelial dysfunction in cerebral arterioles through a mechanism that involves superoxide.


METHODS
Mice heterozygous for a targeted disruption of the cystathionine beta-synthase gene (Cbs+/-) and their wild type littermates (Cbs+/+) were fed either a control diet or a high-methionine diet for 10 to 12 months.


RESULTS
Plasma total homocysteine was elevated with the high-methionine diet compared with the control diet for both Cbs+/+ (7.9+/-1.0 versus 5.0+/-0.5 micromol/L; P<0.05) and Cbs+/- (20.5+/-3.1 versus 8.2+/-0.9 micromol/L; P<0.001) mice. Dilatation of cerebral arterioles ( approximately 30 microm baseline diameter) was measured in vivo in response to the endothelium-dependent dilator acetylcholine or the endothelium-independent dilator nitroprusside. Vasodilatation to acetylcholine was impaired with the high-methionine diet compared with the control diet for both Cbs+/+ and Cbs+/- mice (P<0.01). Dilatation of arterioles to acetylcholine was restored toward normal by the superoxide scavenger tiron (P<0.05). Vasodilatation to nitroprusside was not influenced by Cbs genotype or diet. Dihydroethidium (DHE) staining for vascular superoxide was elevated in Cbs+/- mice fed the high-methionine diet and was inhibited by apocynin or Nomega-nitro-l-arginine methyl ester, implicating NAD(P)H oxidase and nitric oxide synthase as potential sources of superoxide.


CONCLUSIONS
Superoxide is a key mediator of endothelial dysfunction in the cerebral circulation during diet-induced hyperhomocysteinemia.
Dayal
Sanjana
S
Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
Arning
Erland
E
Bottiglieri
Teodoro
T
Böger
Rainer H
RH
Sigmund
Curt D
CD
Faraci
Frank M
FM
Lentz
Steven R
SR
D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000502:physiology; D002561:Cerebrovascular Disorders / Q000209:etiology* / Q000503:physiopathology; D003541:Cystathionine beta-Synthase / Q000235:genetics; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D020138:Hyperhomocysteinemia / Q000150:complications / Q000503:physiopathology*; D008715:Methionine; D051379:Mice; D009599:Nitroprusside / Q000494:pharmacology; D018384:Oxidative Stress; D013481:Superoxides / Q000378:metabolism*; D014664:Vasodilation / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
D014665:Vasodilator Agents; D013481:Superoxides; D009599:Nitroprusside; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D008715:Methionine; D003541:Cystathionine beta-Synthase; D000109:Acetylcholine