on March 7, 2002
Published online before print March 7, 2002, doi: 10.1161/01.ATV.0000014588.71807.0A
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Submitted on January 15, 2002
Accepted on February 15, 2002
Hyperhomocysteinemia Evoked by Folate Depletion. Effects on Coronary and Carotid Arterial Function
J. David Symons *;
From the College of Health (J.D.S.), Department of Exercise and Sport Science, University of Utah, Salt Lake City, Utah; Division of Endocrinology (A.E.M., J.C.R.), Clinical Nutrition, and Vascular Biology; and Department of Nutrition (J.L.E.) and Division of Cardiovascular Medicine (A.A.M.), University of California, Davis, Calif.
* To whom correspondence should be addressed. E-mail: j.david.symons{at}hsc.utah.edu.
Abstract—High
circulating concentrations of homocysteine (ie, hyperhomocysteinemia
[Hhcy]) impair the vascular function of peripheral
conduit arteries and arterioles perfusing splanchnic and skeletal
muscle regions. The effects of HHcy on coronary resistance
vessel function and other indexes of vascular function, ie,
arterial permeability and stiffening, are unclear. We
tested the hypotheses that HHcy impairs coronary resistance
vessel reactivity; increases carotid arterial permeability;
and initiates arterial stiffening. Male rats that consumed
folate-replete (CON, n=44) or folate-deplete (HHcy, n=48) chow for 4 to
5 weeks had total plasma homocysteine concentrations of 7±2 or 58±4
µmol/L, respectively. Maximal acetylcholine-evoked relaxation
(
40% vs 60%) and tension development from baseline in response
to nitric oxide synthase inhibition (20% vs 40%) were lower
(both P<0.05) in
coronary resistance vessels (120 µm, internal diameter)
isolated from HHcy versus CON animals, respectively, whereas sodium
nitroprusside-evoked relaxation and contractile responses to
serotonin and potassium chloride were similar between
groups. Permeability to 4400 MW and 65 000 MW fluorescently
labeled (TRITC) dextran reference macromolecules (quantitative
fluorescence microscopy) was 44% and 24% greater
(P<0.05), respectively, in
carotid arteries from HHcy versus CON rats. Maximal strain, evaluated
by using a vessel elastigraph, was less (32% vs 42%,
P<0.05) in carotid
arterial segments from HHcy versus CON animals,
respectively. Finally, estimates of oxidative (copper-zinc+manganese
superoxide dismutase activity) and glyco-oxidative (pentosidine) stress
were elevated (P<0.05) in
arterial tissue from HHcy versus CON rats. These findings
suggest that moderately severe HHcy evoked by folate-depletion impairs
endothelium-dependent relaxation of coronary
resistance vessels, increases carotid arterial
permeability, and initiates arterial stiffening. HHcy may
produce these effects by a mechanism associated with increased
oxidative and glyco-oxidative stress.