Role of cholesterol-enriched diet and the mevalonate pathway in cardiac nitric oxide synthesis.
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.
Giricz
Zoltán
Z
Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Dóm tér 9, Szeged H-6720, Hungary.
Csonka
Csaba
C
Onody
Annamária
A
Csont
Tamás
T
Ferdinandy
Péter
P
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
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