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Demonstration of rapid onset vascular endothelial dysfunction after hyperhomocysteinemia: an effect reversible with
J C Chambers1, A McGregor, J Jean-Marie
1National Heart and Lung Institute, Imperial College School of Medicine, Hammersmith Hospital, London, UK.
Insights
Elevated homocysteine levels acutely impair vascular endothelial function, a process linked to oxidative stress. Vitamin C pretreatment prevents this dysfunction in healthy individuals, suggesting a protective role against homocysteine-induced vascular damage.
Area of Science:
- Cardiovascular Research
- Vascular Biology
- Nutritional Science
Background:
- Hyperhomocysteinemia is a significant risk factor for vascular disease.
- The precise mechanisms by which homocysteine contributes to atherosclerosis remain unclear.
- Oxidative stress is implicated in homocysteine-mediated endothelial dysfunction.
Purpose of the Study:
- To investigate the association between elevated homocysteine concentrations and acute endothelial dysfunction.
- To determine if vitamin C can prevent homocysteine-induced endothelial dysfunction.
- To explore the role of oxidant stress mechanisms in this process.
Main Methods:
- 17 healthy volunteers underwent oral L-methionine challenge to induce hyperhomocysteinemia.
- Brachial artery diameter responses (endothelium-dependent and independent) were measured using high-resolution ultrasound.
- Measurements were taken at baseline, 2, and 4 hours post-methionine, with and without vitamin C pretreatment.
Main Results:
- Oral L-methionine significantly increased plasma homocysteine levels and reduced flow-mediated dilatation.
- A strong inverse correlation was observed between homocysteine concentration and flow-mediated dilatation.
- Vitamin C pretreatment did not alter homocysteine levels but significantly ameliorated the reduction in flow-mediated dilatation.
Conclusions:
- Acute elevation of homocysteine impairs vascular endothelial function in healthy subjects.
- Vitamin C pretreatment effectively prevents this acute endothelial dysfunction.
- These findings support the hypothesis that homocysteine exerts adverse vascular effects via oxidative stress mechanisms.
Background:
Hyperhomocysteinemia is a major and independent risk factor for vascular disease. The mechanisms by which homocysteine promotes atherosclerosis are not well understood. We hypothesized that elevated homocysteine concentrations are associated with rapid onset endothelial dysfunction, which is mediated through oxidant stress mechanisms and can be inhibited by the antioxidant vitamin C.
Methods And Results:
We studied 17 healthy volunteers (10 male and 7 female) aged 33 (range 21 to 59) years. Brachial artery diameter responses to hyperemic flow (endothelium dependent), and glyceryltrinitrate (GTN, endothelium independent) were measured with high resolution ultrasound at 0 hours (fasting), 2 hours, and 4 hours after (1) oral methionine (L-methionine 100 mg/kg), (2) oral methionine preceded by vitamin C (1g/day, for 1 week), and (3) placebo, on separate days and in random order. Plasma homocysteine increased (0 hours, 12.8+/-1.4; 2 hours, 25.4+/-2.5; and 4 hours, 31. 2+/-3.1 micromol/l, P<0.001), and flow-mediated dilatation fell (0 hours, 4.3+/-0.7; 2 hours, 1.1+/-0.9; and 4 hours, -0.7+/-0.8%) after oral L-methionine. There was an inverse linear relationship between homocysteine concentration and flow-mediated dilatation (P<0. 001). Pretreatment with vitamin C did not affect the rise in homocysteine concentrations after methionine (0 hours, 13.6+/-1.6; 2 hours, 28.3+/-2.9; and 4 hours, 33.8+/-3.7 micromol/l, P=0.27), but did ameliorate the reduction in flow-mediated dilatation (0 hours, 4. 0+/-1.0; 2 hours, 3.5+/-1.2 and 4 hours, 2.8+/-0.7%, P=0.02). GTN-induced endothelium independent brachial artery dilatation was not affected after methionine or methionine preceded by vitamin C.
Conclusions:
We conclude that an elevation in homocysteine concentration is associated with an acute impairment of vascular endothelial function that can be prevented by pretreatment with vitamin C in healthy subjects. Our results support the hypothesis that the adverse effects of homocysteine on vascular endothelial cells are mediated through oxidative stress mechanisms.
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