title: Role of cholesterol-enriched diet and the mevalonate pathway in cardiac nitric oxide synthesis.
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 x 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 Ca(2+)-dependent NOS was unaffected by cholesterol-diet and by treatment with either farnesol or lovastatin, as assessed by (14)C-citrullin assay. Ca(2+)-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.
authors.affiliation: Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Dóm tér 9, Szeged H-6720, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Giricz
authors.forename: Csaba
authors.initials: C
authors.lastname: Csonka
authors.forename: Annamária
authors.initials: A
authors.lastname: Onody
authors.forename: Tamás
authors.initials: T
authors.lastname: Csont
authors.forename: Péter
authors.initials: P
authors.lastname: Ferdinandy
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002791:Cholesterol, Dietary; D004578:Electron Spin Resonance Spectroscopy; D005204:Farnesol / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D006949:Hyperlipidemias / Q000209:etiology / Q000378:metabolism*; D008148:Lovastatin / Q000494:pharmacology; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism
chemical_list: D002791:Cholesterol, Dietary; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013481:Superoxides; D009569:Nitric Oxide; D005204:Farnesol; D008148:Lovastatin; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D008798:Mevalonic Acid