Cerivastatin potentiates nitric oxide release and enos expression through inhibition of isoprenoids synthesis.
Endothelium dysfunction, which is often defined as a decrease in NO bioavailability, is one of the earliest manifestations of endothelium-impaired function disorders, including atherosclerosis. Although improvement in NO bioavailability has been attributed to the lowering of serum cholesterol levels, recent studies suggest that HMG-CoA reductase inhibitors, statins, may have direct effects on NO bioavailability by little known mechanisms that are independent of serum cholesterol levels. The long-term effect of cerivastatin on NO release from endothelial cells was determined by using highly sensitive electrochemical microsensors and was correlated with endothelial NO synthase (eNOS) levels. To explore whether changes in isoprenoid synthesis affect NO bioavailability and eNOS expression, human endothelial cells were treated with cerivastatin, L-mevalonate (MVA; 1.5 mmol/L), geranylgeranylpyrophosphate (GGPP; 1 mg/mL) and farnesylpyrophosphate (FPP; 1 mg/mL). Cerivastatin increased spontaneous (by 53% +/- 6) and an eNOS-stimulated NO release (by 41 +/- 6% for calcium ionophore and by 47 +/- 5% acetylcholine) as well as eNOS expression (by 118 +/- 6%) in the same concentration-range. Cerivastatin-dependent increase in both NO release and eNOS expression was revealed after approximately 4 h of exposure reaching the maximum after approximately 10 h. Co-treatment with MVA or GGPP, but not FPP or LDL, reversed the effects of cerivastatin. These findings indicate that the long-term effect of cerivastatin resulting in enhanced NO bioavailabilty in endothelial cell is, at least in part, due to up-regulation of eNOS by blocking isoprenoids synthesis.
Kalinowski
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L
Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA.
Dobrucki
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IT
Malinski
T
T
D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology*; D011725:Pyridines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D012717:Sesquiterpenes
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D011725:Pyridines; D012717:Sesquiterpenes; D009569:Nitric Oxide; C004808:farnesyl pyrophosphate; C086276:cerivastatin; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid