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Interference in mevalonate pathway ameliorates homocysteine-induced endothelium-dysfunction
Biqi Zhang1, Lihong Qiu, Michael Fu
1Department of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.
European Journal of Pharmacology
|July 17, 2012
Summary
Homocysteine damages blood vessels by affecting cholesterol and oxidative pathways. Targeting these pathways, particularly the mevalonate pathway, can protect endothelial function.
Area of Science:
- Biochemistry
- Cardiovascular Biology
- Cellular Physiology
Background:
- Homocysteine is a known risk factor for atherosclerosis and hypertension.
- Endothelial dysfunction is a critical early event in these cardiovascular diseases.
- Cholesterol accumulation and reactive oxygen species contribute significantly to endothelial damage.
Purpose of the Study:
- To investigate the role of the mevalonate and oxidative pathways in homocysteine-induced endothelial damage.
- To determine if interventions targeting these pathways can protect endothelial function.
Main Methods:
- Isometric tension measurements in rat aortic rings to assess vasorelaxation.
- Measurement of nitric oxide (NO) levels and NO synthase (NOS) activity in endothelial cells.
- Assessment of superoxide anion and cholesterol accumulation.
- Pharmacological interventions using simvastatin, squalestatin, superoxide dismutase, mevalonolactone, and squalene.
Main Results:
- Homocysteine impaired endothelium-dependent vasorelaxation, reduced NO levels and NOS activity, and increased superoxide anion and cholesterol.
- Asymmetric dimethylarginine levels were unaffected by homocysteine.
- Squalestatin and superoxide dismutase partially exacerbated homocysteine's adverse effects.
- Simvastatin completely ameliorated homocysteine-induced endothelial dysfunction.
- Mevalonolactone and squalene modulated the effects of simvastatin and squalestatin, respectively.
Conclusions:
- The mevalonate pathway, in addition to the oxidative pathway, mediates homocysteine-induced endothelial dysfunction.
- Interfering with both the mevalonate and oxidative pathways offers effective protection against endothelial damage caused by homocysteine.
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