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Molecular Pharmacology

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Research ArticleArticle

Activation of the Retinoid X Receptor Modulates Angiotensin II-Induced Smooth Muscle Gene Expression and Inflammation in Vascular Smooth Muscle Cells

Allison M.B. Lehman, John R. Montford, Henrick Horita, Allison C. Ostriker, Mary C.M. Weiser-Evans, Raphael A. Nemenoff and Seth B. Furgeson
Molecular Pharmacology November 2014, 86 (5) 570-579; DOI: https://doi.org/10.1124/mol.114.092163
Allison M.B. Lehman
Division of Renal Diseases and Hypertension (A.L., J.R.M., H.H., A.C.O., M.W.E., R.A.N., S.B.F.), Cardiovascular Pulmonary Research Laboratory, Department of Medicine (M.W.E., R.A.N.), University of Colorado Anschutz Medical Campus, Aurora, Colorado; and Department of Medicine, Denver Health Hospital, Denver, Colorado (S.B.F)
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John R. Montford
Division of Renal Diseases and Hypertension (A.L., J.R.M., H.H., A.C.O., M.W.E., R.A.N., S.B.F.), Cardiovascular Pulmonary Research Laboratory, Department of Medicine (M.W.E., R.A.N.), University of Colorado Anschutz Medical Campus, Aurora, Colorado; and Department of Medicine, Denver Health Hospital, Denver, Colorado (S.B.F)
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Henrick Horita
Division of Renal Diseases and Hypertension (A.L., J.R.M., H.H., A.C.O., M.W.E., R.A.N., S.B.F.), Cardiovascular Pulmonary Research Laboratory, Department of Medicine (M.W.E., R.A.N.), University of Colorado Anschutz Medical Campus, Aurora, Colorado; and Department of Medicine, Denver Health Hospital, Denver, Colorado (S.B.F)
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Allison C. Ostriker
Division of Renal Diseases and Hypertension (A.L., J.R.M., H.H., A.C.O., M.W.E., R.A.N., S.B.F.), Cardiovascular Pulmonary Research Laboratory, Department of Medicine (M.W.E., R.A.N.), University of Colorado Anschutz Medical Campus, Aurora, Colorado; and Department of Medicine, Denver Health Hospital, Denver, Colorado (S.B.F)
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Mary C.M. Weiser-Evans
Division of Renal Diseases and Hypertension (A.L., J.R.M., H.H., A.C.O., M.W.E., R.A.N., S.B.F.), Cardiovascular Pulmonary Research Laboratory, Department of Medicine (M.W.E., R.A.N.), University of Colorado Anschutz Medical Campus, Aurora, Colorado; and Department of Medicine, Denver Health Hospital, Denver, Colorado (S.B.F)
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Raphael A. Nemenoff
Division of Renal Diseases and Hypertension (A.L., J.R.M., H.H., A.C.O., M.W.E., R.A.N., S.B.F.), Cardiovascular Pulmonary Research Laboratory, Department of Medicine (M.W.E., R.A.N.), University of Colorado Anschutz Medical Campus, Aurora, Colorado; and Department of Medicine, Denver Health Hospital, Denver, Colorado (S.B.F)
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Seth B. Furgeson
Division of Renal Diseases and Hypertension (A.L., J.R.M., H.H., A.C.O., M.W.E., R.A.N., S.B.F.), Cardiovascular Pulmonary Research Laboratory, Department of Medicine (M.W.E., R.A.N.), University of Colorado Anschutz Medical Campus, Aurora, Colorado; and Department of Medicine, Denver Health Hospital, Denver, Colorado (S.B.F)
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Abstract

The retinoid X receptor (RXR) partners with numerous nuclear receptors, such as the peroxisome proliferator activated receptor (PPAR) family, liver X receptors (LXRs), and farnesoid X receptor (FXR). Although each heterodimer can be activated by specific ligands, a subset of these receptors, defined as permissive nuclear receptors, can also be activated by RXR agonists known as rexinoids. Many individual RXR heterodimers have beneficial effects in vascular smooth muscle cells (SMCs). Because rexinoids can potently activate multiple RXR pathways, we hypothesized that treating SMCs with rexinoids would more effectively reverse the pathophysiologic effects of angiotensin II than an individual heterodimer agonist. Cultured rat aortic SMCs were pretreated with either an RXR agonist (bexarotene or 9-cis retinoic acid) or vehicle (dimethylsulfoxide) for 24 hours before stimulation with angiotensin II. Compared with dimethylsulfoxide, bexarotene blocked angiotensin II-induced SM contractile gene induction (calponin and smooth muscle-α-actin) and protein synthesis ([3H]leucine incorporation). Bexarotene also decreased angiotensin II-mediated inflammation, as measured by decreased expression of monocyte chemoattractant protein-1 (MCP-1). Activation of p38 mitogen-activated protein (MAP) kinase but not extracellular signal-related kinase (ERK) or protein kinase B (Akt) was also blunted by bexarotene. We compared bexarotene to five agonists of nuclear receptors (PPARα, PPARγ, PPARδ, LXR, and FXR). Bexarotene had a greater effect on calponin reduction, MCP-1 inhibition, and p38 MAP kinase inhibition than any individual agonist. PPARγ knockout cells demonstrated blunted responses to bexarotene, indicating that PPARγ is necessary for the effects of bexarotene. These data demonstrate that RXR is a potent modulator of angiotensin II-mediated responses in the vasculature, partially through inhibition of p38.

Footnotes

    • Received February 11, 2014.
    • Accepted August 28, 2014.
  • This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grants 2P01-HL014985, 1R01-HL88643, K08-HL103774]; and National Institute of Diabetes and Digestive and Kidney Diseases [Grant T32-DK7135].

  • dx.doi.org/10.1124/mol.114.092163.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 86 (5)
Molecular Pharmacology
Vol. 86, Issue 5
1 Nov 2014
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Research ArticleArticle

RXR Agonist Inhibits AII Hypertrophy and Inflammation

Allison M.B. Lehman, John R. Montford, Henrick Horita, Allison C. Ostriker, Mary C.M. Weiser-Evans, Raphael A. Nemenoff and Seth B. Furgeson
Molecular Pharmacology November 1, 2014, 86 (5) 570-579; DOI: https://doi.org/10.1124/mol.114.092163

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Research ArticleArticle

RXR Agonist Inhibits AII Hypertrophy and Inflammation

Allison M.B. Lehman, John R. Montford, Henrick Horita, Allison C. Ostriker, Mary C.M. Weiser-Evans, Raphael A. Nemenoff and Seth B. Furgeson
Molecular Pharmacology November 1, 2014, 86 (5) 570-579; DOI: https://doi.org/10.1124/mol.114.092163
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