title: Activation of the retinoid X receptor modulates angiotensin II-induced smooth muscle gene expression and inflammation in vascular smooth muscle cells.
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 ([(3)H]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.
authors.affiliation: 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).
authors.forename: Allison M B
authors.initials: AM
authors.lastname: Lehman
authors.affiliation: 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).
authors.forename: John R
authors.initials: JR
authors.lastname: Montford
authors.affiliation: 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).
authors.forename: Henrick
authors.initials: H
authors.lastname: Horita
authors.affiliation: 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).
authors.forename: Allison C
authors.initials: AC
authors.lastname: Ostriker
authors.affiliation: 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).
authors.forename: Mary C M
authors.initials: MC
authors.lastname: Weiser-Evans
authors.affiliation: 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).
authors.forename: Raphael A
authors.initials: RA
authors.lastname: Nemenoff
authors.affiliation: 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) seth.furgeson@ucdenver.edu.
authors.forename: Seth B
authors.initials: SB
authors.lastname: Furgeson
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000077610:Bexarotene; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics*; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D047488:Retinoid X Receptors / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000096985:Calponins
chemical_list: D000199:Actins; D000804:Angiotensin II; D000077610:Bexarotene; D002135:Calcium-Binding Proteins; D018932:Chemokine CCL2; D008840:Microfilament Proteins; D047495:PPAR gamma; D051057:Proto-Oncogene Proteins c-akt; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D048051:p38 Mitogen-Activated Protein Kinases; D000096985:Calponins; C491766:Ccl2 protein, rat