Circulation Research. 2001;88:1203-1209
Published online before print May 24, 2001, doi: 10.1161/hh1101.092180
Published online before print May 24, 2001, doi: 10.1161/hh1101.092180
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© 2001 American Heart Association, Inc.
Integrative Physiology |
Endothelial Dysfunction and Elevation of S-Adenosylhomocysteine in Cystathionine ß-Synthase–Deficient Mice
From the Departments of Internal Medicine (S.D., C.D.S., D.D.H., F.M.F., S.R.L.), Pharmacology (D.D.H., F.M.F.), and Physiology and Biophysics (C.D.S.), University of Iowa College of Medicine, Iowa City, Iowa; Veterans Affairs Medical Center (D.D.H., S.R.L.), Iowa City, Iowa; Baylor Institute of Metabolic Disease (T.B., E.A.), Dallas, Tex; Department of Pathology (N.M.), University of North Carolina, Chapel Hill, NC; Oregon Regional Primate Research Center (M.R.M.), Beaverton, Oreg.
Correspondence to Steven R. Lentz, MD, PhD, Department of Internal Medicine, C303 GH, The University of Iowa, Iowa City, IA 52242. E-mail steven-lentz{at}uiowa.edu
Abstract
Abstract—Hyperhomocysteinemia
is associated with increased risk for cardiovascular
events, but it is not certain whether it is a mediator of vascular
dysfunction or a marker for another risk factor. Homocysteine levels
are regulated by folate bioavailability and also by the methyl donor
S-adenosylmethionine (SAM) and
its metabolite
S-adenosylhomocysteine (SAH).
We tested the hypotheses that endothelial dysfunction
occurs in hyperhomocysteinemic mice in the absence of folate deficiency
and that levels of SAM and SAH are altered in mice with dysfunction.
Heterozygous cystathionine ß-synthase–deficient
(CBS+/–) and wild-type
(CBS+/+) mice were fed a folate-replete,
methionine-enriched diet. Plasma levels of total homocysteine were
elevated in CBS+/– mice compared with
CBS+/+ mice after 7 weeks (27.1±5.2 versus
8.8±1.1 µmol/L; P<0.001)
and 15 weeks (23.9±3.0 versus 13.0±2.3 µmol/L;
P<0.01). After 15 weeks, but
not 7 weeks, relaxation of aortic rings to acetylcholine was
selectively impaired by 35%
(P<0.05) and thrombomodulin
anticoagulant activity was decreased by 20%
(P<0.05) in
CBS+/– mice. Plasma levels of folate did
not differ between groups. Levels of SAH were elevated 
2-fold in
liver and brain of CBS+/– mice, and
correlations were observed between plasma total homocysteine and SAH in
liver (r=0.54;
P<0.001) and brain
(r=0.67;
P<0.001). These results
indicate that endothelial dysfunction occurs in
hyperhomocysteinemic mice even in the absence of folate deficiency.
Endothelial dysfunction in
CBS+/– mice was associated with increased
tissue levels of SAH, which suggests that altered SAM-dependent
methylation may contribute to vascular dysfunction in
hyperhomocysteinemia.
Key Words: acetylcholine • endothelium • homocysteine • methylation • thrombomodulin
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