Related Experiment Videos
Folate dependence of hyperhomocysteinemia and vascular dysfunction in cystathionine beta-synthase-deficient mice
S R Lentz1, R A Erger, S Dayal
1Veterans Affairs Medical Center, Iowa City 52246, USA. steven-lentz@uiowa.edu
Insights
Moderate hyperhomocysteinemia, a risk factor for cardiovascular events, impairs endothelial function. This study shows that cystathionine beta-synthase deficient mice develop hyperhomocysteinemia on a low-folate diet, leading to significant endothelial dysfunction.
Area of Science:
- Cardiovascular Science
- Metabolic Disorders
- Vascular Biology
Background:
- Hyperhomocysteinemia is a known risk factor for cardiovascular diseases like stroke and myocardial infarction.
- The mechanisms linking hyperhomocysteinemia to endothelial dysfunction are not fully understood.
- Endothelial dysfunction contributes to the pathogenesis of various cardiovascular conditions.
Purpose of the Study:
- To investigate the relationship between moderate hyperhomocysteinemia and endothelial dysfunction using a mouse model.
- To elucidate the mechanisms underlying endothelial dysfunction in the context of elevated homocysteine levels.
- To assess the impact of dietary folate deficiency on homocysteine levels and vascular function.
Main Methods:
- Genetic modification: Used heterozygous cystathionine beta-synthase-deficient (CBS +/-) mice and wild-type (CBS +/+) littermates.
- Dietary intervention: Fed mice either a control diet or a diet deficient in folic acid for 6 weeks.
- Vascular function assessment: Measured aortic ring relaxation in response to acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent) vasodilators.
Main Results:
- Dietary folate deficiency significantly increased plasma homocysteine levels in CBS +/- mice compared to controls.
- CBS +/- mice on a low-folate diet exhibited impaired relaxation to acetylcholine, indicating endothelial dysfunction.
- No significant differences in relaxation to sodium nitroprusside were observed, suggesting the dysfunction is endothelium-specific.
Conclusions:
- CBS-deficient mice are susceptible to diet-induced hyperhomocysteinemia.
- Moderate hyperhomocysteinemia, particularly when induced by folate deficiency, is associated with significant endothelial dysfunction in mice.
- These findings highlight the detrimental role of homocysteine in vascular health and suggest potential therapeutic targets.
Abstract:
Hyperhomocysteinemia is a risk factor for stroke, myocardial infarction, and venous thrombosis. Moderate hyperhomocysteinemia is associated with impaired endothelial function, but the mechanisms responsible for endothelial dysfunction in hyperhomocysteinemia are poorly understood. We have used genetic and dietary approaches to produce hyperhomocysteinemia in mice. Heterozygous cystathionine beta-synthase-deficient mice (CBS +/-), which have a selective defect in homocysteine transsulfuration, and wild-type (CBS +/+) littermates were fed either a control diet or a diet that is relatively deficient in folic acid for 6 wk. Plasma total homocysteine was 5.3 +/- 0.7 microM in CBS +/+ mice and 6.4 +/- 0.6 microM in CBS +/- mice (P = 0.3) given the control diet. Plasma total homocysteine was 11.6 +/- 4.5 microM in CBS +/+ mice and 25.1 +/- 3.2 microM in CBS +/- mice (P = 0.004) given a low-folate diet. In mice fed the control diet, relaxation of aortic rings in response to the endothelium-dependent vasodilator acetylcholine did not differ significantly between CBS +/+ mice and CBS +/- mice. In contrast, in mice fed a low-folate diet, maximal relaxation to acetylcholine was markedly impaired in CBS +/- mice (58 +/- 9%) compared with CBS +/+ mice (84 +/- 4%) (P = 0.01). No differences in relaxation to the endothelium-independent vasodilator sodium nitroprusside were observed among the four groups of mice. These data indicate that CBS-deficient mice are predisposed to hyperhomocysteinemia during dietary folate deficiency, and moderate hyperhomocysteinemia is associated with marked impairment of endothelial function in mice.