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3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors upregulate inducible NO synthase expression and activity in vascular smooth muscle cells.
Hypertension 2001; 38(5):1024-9H

Abstract

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase ameliorate atherosclerosis by both cholesterol-dependent and cholesterol-independent mechanisms. We examined whether HMG-CoA reductase inhibitors affect the expression and activity of inducible NO synthase (iNOS) in cultured rat aortic vascular smooth muscle (VSM) cells. Atorvastatin (34 to 68 micromol/L) markedly increased nitrite production, an increase that was essentially abrogated by the NO synthase inhibitor N(G)-monomethyl-L-arginine (500 micromol/L). Activity of iNOS, determined by the conversion of L-arginine to L-citrulline, increased 9-fold after atorvastatin treatment. Western blot and semiquantitative reverse transcriptase-polymerase chain reaction revealed that atorvastatin (34 to 68 micromol/L) strongly upregulated iNOS protein and mRNA levels, respectively. These concentrations of atorvastatin did not cause cytotoxicity, as judged by the cell survival rate. Similarly, simvastatin and lovastatin (34 micromol/L) caused robust upregulation of the iNOS protein level. Transfection experiments demonstrated that the -1034- to 88-bp human iNOS promoter was strongly induced by atorvastatin (34 micromol/L). Electromobility and supershift assays using a nuclear factor-kappaB (NF-kappaB) consensus oligonucleotide and nuclear extracts from VSM cells as well as transfection studies using an NF-kappaB reporter plasmid suggested that the transcriptional activation of the iNOS gene by atorvastatin is not mediated via the NF-kappaB pathway. We conclude that HMG-CoA reductase inhibitors potently upregulate iNOS expression and activity in VSM cells, at least in part, by transcriptional mechanisms that do not depend on transcription factor NF-kappaB. These effects might have important implications for the impact of HMG-CoA reductase inhibitors on atherosclerosis.

Authors+Show Affiliations

Department of Medicine, Tufts University School of Medicine, Division of Nephrology and the Tupper Research Institute, New England Medical Center, Boston, Massachusetts, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

11711492

Citation

Kolyada, A Y., et al. "3-hydroxy-3-methylglutaryl Coenzyme a Reductase Inhibitors Upregulate Inducible NO Synthase Expression and Activity in Vascular Smooth Muscle Cells." Hypertension (Dallas, Tex. : 1979), vol. 38, no. 5, 2001, pp. 1024-9.
Kolyada AY, Fedtsov A, Madias NE. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors upregulate inducible NO synthase expression and activity in vascular smooth muscle cells. Hypertension. 2001;38(5):1024-9.
Kolyada, A. Y., Fedtsov, A., & Madias, N. E. (2001). 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors upregulate inducible NO synthase expression and activity in vascular smooth muscle cells. Hypertension (Dallas, Tex. : 1979), 38(5), pp. 1024-9.
Kolyada AY, Fedtsov A, Madias NE. 3-hydroxy-3-methylglutaryl Coenzyme a Reductase Inhibitors Upregulate Inducible NO Synthase Expression and Activity in Vascular Smooth Muscle Cells. Hypertension. 2001;38(5):1024-9. PubMed PMID: 11711492.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors upregulate inducible NO synthase expression and activity in vascular smooth muscle cells. AU - Kolyada,A Y, AU - Fedtsov,A, AU - Madias,N E, PY - 2001/11/17/pubmed PY - 2002/1/5/medline PY - 2001/11/17/entrez SP - 1024 EP - 9 JF - Hypertension (Dallas, Tex. : 1979) JO - Hypertension VL - 38 IS - 5 N2 - Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase ameliorate atherosclerosis by both cholesterol-dependent and cholesterol-independent mechanisms. We examined whether HMG-CoA reductase inhibitors affect the expression and activity of inducible NO synthase (iNOS) in cultured rat aortic vascular smooth muscle (VSM) cells. Atorvastatin (34 to 68 micromol/L) markedly increased nitrite production, an increase that was essentially abrogated by the NO synthase inhibitor N(G)-monomethyl-L-arginine (500 micromol/L). Activity of iNOS, determined by the conversion of L-arginine to L-citrulline, increased 9-fold after atorvastatin treatment. Western blot and semiquantitative reverse transcriptase-polymerase chain reaction revealed that atorvastatin (34 to 68 micromol/L) strongly upregulated iNOS protein and mRNA levels, respectively. These concentrations of atorvastatin did not cause cytotoxicity, as judged by the cell survival rate. Similarly, simvastatin and lovastatin (34 micromol/L) caused robust upregulation of the iNOS protein level. Transfection experiments demonstrated that the -1034- to 88-bp human iNOS promoter was strongly induced by atorvastatin (34 micromol/L). Electromobility and supershift assays using a nuclear factor-kappaB (NF-kappaB) consensus oligonucleotide and nuclear extracts from VSM cells as well as transfection studies using an NF-kappaB reporter plasmid suggested that the transcriptional activation of the iNOS gene by atorvastatin is not mediated via the NF-kappaB pathway. We conclude that HMG-CoA reductase inhibitors potently upregulate iNOS expression and activity in VSM cells, at least in part, by transcriptional mechanisms that do not depend on transcription factor NF-kappaB. These effects might have important implications for the impact of HMG-CoA reductase inhibitors on atherosclerosis. SN - 1524-4563 UR - https://www.unboundmedicine.com/medline/citation/11711492/3_hydroxy_3_methylglutaryl_coenzyme_A_reductase_inhibitors_upregulate_inducible_NO_synthase_expression_and_activity_in_vascular_smooth_muscle_cells_ L2 - http://www.ahajournals.org/doi/full/10.1161/hy1101.093103?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -