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Fluvastatin ameliorates the hyperhomocysteinemia-induced endothelial dysfunction: the antioxidative properties of
Hiroyuki Morita1, Yuichiro Saito, Noriko Ohashi
1Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Insights
High homocysteine levels cause oxidative stress and impair blood vessel function. The antioxidant drug fluvastatin effectively reduced this oxidative stress, improving endothelial dysfunction in hyperhomocysteinemic rats.
Area of Science:
- Cardiovascular Science
- Oxidative Stress Research
- Pharmacology
Background:
- Hyperhomocysteinemia is linked to vascular endothelial dysfunction and atherosclerosis.
- Oxidative stress is a primary mechanism for homocysteine's adverse vascular effects.
- Statins, like fluvastatin, possess antioxidant properties.
Purpose of the Study:
- To investigate if the antioxidant properties of fluvastatin can counteract hyperhomocysteinemia-induced endothelial dysfunction.
- To evaluate fluvastatin's efficacy in reducing oxidative stress markers in hyperhomocysteinemia.
Main Methods:
- Diet-induced hyperhomocysteinemic rat model.
- Measurement of urinary 8-isoprostaglandin F2alpha-III excretion and vascular superoxide generation.
- Assessment of endothelium-dependent vasodilatation.
- Administration of fluvastatin or vitamin E as antioxidants.
Main Results:
- Hyperhomocysteinemia significantly increased oxidative stress markers and impaired endothelial function.
- Fluvastatin and vitamin E normalized oxidative stress levels.
- Both antioxidants ameliorated the endothelial dysfunction caused by hyperhomocysteinemia.
Conclusions:
- Mild to moderate hyperhomocysteinemia induces endothelial dysfunction via oxidative stress.
- Antioxidant fluvastatin effectively mitigated oxidative stress and improved endothelial function in this model.
- Fluvastatin may be a therapeutic strategy for hyperhomocysteinemia, complementing folate therapy and addressing hyperlipidemia.
Background:
Hyperhomocysteinemia induces vascular endothelial dysfunction, contributing to a predisposition to the onset and/or progression of atherosclerosis. The major mechanism suggested for the adverse effect of homocysteine on vascular function seems to involve oxidative stress. Thus, we hypothesized that the administration of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin, which is experimentally demonstrated to have antioxidative properties as one of its pleiotropic effects, is a useful strategy for eliminating the detrimental events induced by hyperhomocysteinemia.
Methods And Results:
In diet-induced hyperhomocysteinemic rats, we estimated oxidative stress and assessed endothelium-dependent vasodilatation. Hyperhomocysteinemia induced significant increases in urinary 8-isoprostaglandin F2alpha-III excretion and vascular superoxide generation, and impaired endothelium-dependent vasodilatation. Additional oral administration of the antioxidant fluvastatin or vitamin E, which normalized increased oxidative stress induced by hyperhomocysteinemia, ameliorated endothelial dysfunction.
Conclusions:
Hyperhomocysteinemia, even mild to moderate, induces endothelial dysfunction through its oxidative effect. The antioxidant fluvastatin was able to cancel out the oxidative stress induced by hyperhomocysteinemia and ameliorate endothelial dysfunction. Clinical use of fluvastatin might be a potent strategy for eliminating the detrimental events induced by hyperhomocysteinemia as well as hyperlipidemia. In addition to lowering homocysteine by means of folate supplementation, administration of the antioxidants is expected to be a potentially effective anti-homocysteine therapy.
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