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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.JCI

Abstract

Endothelial dysfunction associated with atherosclerosis has been attributed to alterations in the L-arginine-nitric oxide (NO)-cGMP pathway or to an excess of endothelin-1 (ET-1). The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to ameliorate endothelial function. However, the physiological basis of this observation is largely unknown. We investigated the effects of Atorvastatin and Simvastatin on the pre-proET-1 mRNA expression and ET-1 synthesis and on the endothelial NO synthase (eNOS) transcript and protein levels in bovine aortic endothelial cells. These agents inhibited pre-proET-1 mRNA expression in a concentration- and time-dependent fashion (60-70% maximum inhibition) and reduced immunoreactive ET-1 levels (25-50%). This inhibitory effect was maintained in the presence of oxidized LDL (1-50 microg/ml). No significant modification of pre-proET-1 mRNA half-life was observed. In addition, mevalonate, but not cholesterol, reversed the statin-mediated decrease of pre-proET-1 mRNA levels. eNOS mRNA expression was reduced by oxidized LDL in a dose-dependent fashion (up to 57% inhibition), whereas native LDL had no effect. Statins were able to prevent the inhibitory action exerted by oxidized LDL on eNOS mRNA and protein levels. Hence, these drugs might influence vascular tone by modulating the expression of endothelial vasoactive factors.

Authors+Show Affiliations

Centro de Investigaciones Biológicas, Instituto Reina Sofía de Investigaciones Nefrológicas, Consejo Superior de Investigaciones Científicas, 28006 Madrid, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9637705

Citation

Hernández-Perera, O, et al. "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." The Journal of Clinical Investigation, vol. 101, no. 12, 1998, pp. 2711-9.
Hernández-Perera O, Pérez-Sala D, Navarro-Antolín J, et al. 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;101(12):2711-9.
Hernández-Perera, O., Pérez-Sala, D., Navarro-Antolín, J., Sánchez-Pascuala, R., Hernández, G., Díaz, C., & Lamas, S. (1998). 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. The Journal of Clinical Investigation, 101(12), 2711-9.
Hernández-Perera O, et al. 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. PubMed PMID: 9637705.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Hernández-Perera,O, AU - Pérez-Sala,D, AU - Navarro-Antolín,J, AU - Sánchez-Pascuala,R, AU - Hernández,G, AU - Díaz,C, AU - Lamas,S, PY - 1998/6/24/pubmed PY - 1998/6/24/medline PY - 1998/6/24/entrez SP - 2711 EP - 9 JF - The Journal of clinical investigation JO - J Clin Invest VL - 101 IS - 12 N2 - Endothelial dysfunction associated with atherosclerosis has been attributed to alterations in the L-arginine-nitric oxide (NO)-cGMP pathway or to an excess of endothelin-1 (ET-1). The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to ameliorate endothelial function. However, the physiological basis of this observation is largely unknown. We investigated the effects of Atorvastatin and Simvastatin on the pre-proET-1 mRNA expression and ET-1 synthesis and on the endothelial NO synthase (eNOS) transcript and protein levels in bovine aortic endothelial cells. These agents inhibited pre-proET-1 mRNA expression in a concentration- and time-dependent fashion (60-70% maximum inhibition) and reduced immunoreactive ET-1 levels (25-50%). This inhibitory effect was maintained in the presence of oxidized LDL (1-50 microg/ml). No significant modification of pre-proET-1 mRNA half-life was observed. In addition, mevalonate, but not cholesterol, reversed the statin-mediated decrease of pre-proET-1 mRNA levels. eNOS mRNA expression was reduced by oxidized LDL in a dose-dependent fashion (up to 57% inhibition), whereas native LDL had no effect. Statins were able to prevent the inhibitory action exerted by oxidized LDL on eNOS mRNA and protein levels. Hence, these drugs might influence vascular tone by modulating the expression of endothelial vasoactive factors. SN - 0021-9738 UR - https://www.unboundmedicine.com/medline/citation/9637705/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_ L2 - https://doi.org/10.1172/JCI1500 DB - PRIME DP - Unbound Medicine ER -