Hydroxy-methylglutaryl-coenzyme A reductase inhibition promotes endothelial nitric oxide synthase activation through a decrease in caveolin abundance
- PMID: 11136695
- DOI: 10.1161/01.cir.103.1.113
Hydroxy-methylglutaryl-coenzyme A reductase inhibition promotes endothelial nitric oxide synthase activation through a decrease in caveolin abundance
Abstract
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.
Methods and 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.
Comment in
-
Cracking down on caveolin: role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in modulating edothelial cell nitric oxide production.Circulation. 2001 Jan 2;103(1):2-4. doi: 10.1161/01.cir.103.1.2. Circulation. 2001. PMID: 11136674 No abstract available.
Similar articles
-
Hsp90 and caveolin are key targets for the proangiogenic nitric oxide-mediated effects of statins.Circ Res. 2001 Nov 9;89(10):866-73. doi: 10.1161/hh2201.100319. Circ Res. 2001. PMID: 11701613
-
Signal transduction of eNOS activation.Cardiovasc Res. 1999 Aug 15;43(3):532-41. doi: 10.1016/s0008-6363(99)00094-2. Cardiovasc Res. 1999. PMID: 10690325 Review.
-
Cholesterol-dependent regulation of nitric oxide production: potential role in atherosclerosis.Nutr Rev. 1999 Sep;57(9 Pt 1):279-82. doi: 10.1111/j.1753-4887.1999.tb01812.x. Nutr Rev. 1999. PMID: 10568338 Review.
-
Hypercholesterolemia decreases nitric oxide production by promoting the interaction of caveolin and endothelial nitric oxide synthase.J Clin Invest. 1999 Mar;103(6):897-905. doi: 10.1172/JCI4829. J Clin Invest. 1999. PMID: 10079111 Free PMC article.
-
Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells.J Clin Invest. 1998 Jun 15;101(12):2711-9. doi: 10.1172/JCI1500. J Clin Invest. 1998. PMID: 9637705 Free PMC article.
Cited by
-
Brain cholesterol and Alzheimer's disease: challenges and opportunities in probe and drug development.Brain. 2024 May 3;147(5):1622-1635. doi: 10.1093/brain/awae028. Brain. 2024. PMID: 38301270 Review.
-
Facts and ideas on statins with respect to their lipophilicity: a focus on skeletal muscle cells and bone besides known cardioprotection.Mol Cell Biochem. 2023 Aug;478(8):1661-1667. doi: 10.1007/s11010-022-04621-y. Epub 2022 Dec 5. Mol Cell Biochem. 2023. PMID: 36471123 Free PMC article. Review.
-
Association between single nucleotide polymorphism SLCO1B1 gene and simvastatin pleiotropic effects measured through flow-mediated dilation endothelial function parameters.Ther Adv Cardiovasc Dis. 2022 Jan-Dec;16:17539447221132367. doi: 10.1177/17539447221132367. Ther Adv Cardiovasc Dis. 2022. PMID: 36314075 Free PMC article.
-
Pharmacogenomics of cisplatin-induced neurotoxicities: Hearing loss, tinnitus, and peripheral sensory neuropathy.Cancer Med. 2022 Jul;11(14):2801-2816. doi: 10.1002/cam4.4644. Epub 2022 Mar 23. Cancer Med. 2022. PMID: 35322580 Free PMC article.
-
Beneficial Effect of Statin Therapy on Arterial Stiffness.Biomed Res Int. 2021 Mar 30;2021:5548310. doi: 10.1155/2021/5548310. eCollection 2021. Biomed Res Int. 2021. PMID: 33860033 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical