Hydroxy-methylglutaryl-coenzyme A reductase inhibition promotes endothelial nitric oxide synthase activation through a decrease in caveolin abundance.
BACKGROUND
Hypercholesterolemia is causally associated with defects of endothelial nitric oxide (NO)-dependent vasodilation. Increased uptake of cholesterol by endothelial cells (ECs) upregulates the abundance of the structural protein caveolin-1 and impairs NO release through the stabilization of the inhibitory heterocomplex between caveolin-1 and endothelial NO synthase (eNOS). Therefore, we examined whether the hydroxy-methylglutaryl-coenzyme A reductase inhibitor atorvastatin modulates caveolin abundance, eNOS activity, and NO release through a reduction in endogenous cholesterol levels.


RESULTS
ECs were incubated with increasing doses of atorvastatin in the absence or in the presence of human LDL cholesterol (LDL-Chol) fractions in the presence of antioxidants. Our results show that atorvastatin (10 nmol/L to 1 micromol/L) reduced caveolin-1 abundance in the absence (-75%) and in the presence (-20% to 70%) of LDL-Chol. This was paralleled by a decreased inhibitory interaction between caveolin-1 and eNOS and a restoration and/or potentiation of the basal (+45%) and agonist-stimulated (+107%) eNOS activity. These effects were observed in the absence of changes in eNOS abundance and were reversed with mevalonate. In the presence of LDL-Chol, atorvastatin also promoted the agonist-induced association of eNOS and the chaperone Hsp90, resulting in the potentiation of eNOS activation.


CONCLUSIONS
We provide biochemical and functional evidence that atorvastatin promotes NO production by decreasing caveolin-1 expression in ECs, regardless of the level of extracellular LDL-Chol. These findings highlight the therapeutic potential of inhibiting cholesterol synthesis in peripheral cells to correct NO-dependent endothelial dysfunction associated with hypercholesterolemia and possibly other diseases.
Feron
O
O
Department of Medicine, Unit of Pharmacology and Therapeutics, University of Louvain Medical School, Brussels, Belgium.
Dessy
C
C
Desager
J P
JP
Balligand
J L
JL
D000818:Animals; D000069059:Atorvastatin; D022762:CCAAT-Enhancer-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002417:Cattle; D051242:Caveolin 1; D022461:Caveolins / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis; D008078:Cholesterol, LDL / Q000378:metabolism / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007976:Leupeptins / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D011758:Pyrroles / Q000494:pharmacology; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D015854:Up-Regulation / Q000187:drug effects
C495540:CAV1 protein, human; D022762:CCAAT-Enhancer-Binding Proteins; D051242:Caveolin 1; D022461:Caveolins; D008078:Cholesterol, LDL; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007976:Leupeptins; D008077:Lipoproteins, LDL; D011758:Pyrroles; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; C063261:acetylleucyl-leucyl-norleucinal; D009569:Nitric Oxide; D002784:Cholesterol; D000069059:Atorvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III