Abstract.
Cardiac stress adaptation is deteriorated in hyperlipidemia possibly due to deterioration of nitric oxide (NO) metabolism. However, inhibition of HMG-CoA reductase, a key enzyme in the mevalonate pathway, was shown to increase the level of endothelial NO-synthase (eNOS) mRNA. Here we studied the effect of dietary and pharmacologic modulation of the mevalonate pathway on cardiac NO synthesis. Rats were fed 2% cholesterol-enriched or normal diet for 8 weeks. Normal and cholesterol-fed animals were treated with farnesol, a major metabolite of the mevalonate pathway (2.2 mg/kg i.p.) or with the HMG-CoA reductase inhibitor lovastatin (3 × 5 mg/kg per os for 3 days, n = 5–6 in each group). Cardiac NO content was significantly decreased in cholesterol-fed rats as assessed by electron spin resonance spectroscopy, however, other treatments did not influence cardiac NO content. Cardiac activity of Ca2+-dependent NOS was unaffected by cholesterol-diet and by treatment with either farnesol or lovastatin, as assessed by 14C-citrullin assay. Ca2+-independent NOS activity was negligible in all groups. Cardiac eNOS protein content measured by Western blotting was also unchanged in all groups. We conclude that cholesterol-diet decreases cardiac NO content, however, cholesterol diet-induced inhibition of the mevalonate pathway does not account for the decreased NO level in the heart, and that the mevalonate pathway does not influence cardiac NO biosynthesis.
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Giricz, Z., Csonka, C., Ónody, A. et al. Role of cholesterol-enriched diet and the mevalonate pathway in cardiac nitric oxide synthesis. Basic Res Cardiol 98, 304–310 (2003). https://doi.org/10.1007/s00395-003-0412-0
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DOI: https://doi.org/10.1007/s00395-003-0412-0