Lehman Allison M B, Montford John R, Horita Henrick, Ostriker Allison C, Weiser-Evans Mary C M, Nemenoff Raphael A, Furgeson Seth B
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).
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)
Mol Pharmacol. 2014 Nov;86(5):570-9. doi: 10.1124/mol.114.092163. Epub 2014 Aug 28.
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.
视黄酸X受体（RXR）可与多种核受体形成异源二聚体，如过氧化物酶体增殖物激活受体（PPAR）家族、肝X受体（LXR）和法尼酯X受体（FXR）。尽管每种异源二聚体均可被特定配体激活，但其中一部分受体（即所谓的允许性核受体）也可被称为视黄酸类药物的RXR激动剂激活。许多单个的RXR异源二聚体对血管平滑肌细胞（SMC）具有有益作用。由于视黄酸类药物可有效激活多条RXR信号通路，我们推测用视黄酸类药物处理SMC比使用单个异源二聚体激动剂能更有效地逆转血管紧张素II的病理生理效应。培养的大鼠主动脉SMC在接受血管紧张素II刺激前24小时，先用RXR激动剂（贝沙罗汀或9-顺式维甲酸）或溶剂（二甲基亚砜）进行预处理。与二甲基亚砜相比，贝沙罗汀可阻断血管紧张素II诱导的平滑肌收缩基因（钙调蛋白和平滑肌α-肌动蛋白）的表达及蛋白质合成（[³H]亮氨酸掺入）。贝沙罗汀还可减轻血管紧张素II介导的炎症反应，这可通过单核细胞趋化蛋白-1（MCP-1）表达降低来衡量。贝沙罗汀还可减弱p38丝裂原活化蛋白（MAP）激酶的激活，但对细胞外信号调节激酶（ERK）或蛋白激酶B（Akt）无影响。我们将贝沙罗汀与五种核受体激动剂（PPARα、PPARγ、PPARδ、LXR和FXR）进行了比较。贝沙罗汀在降低钙调蛋白、抑制MCP-1及抑制p38 MAP激酶方面比任何一种单个激动剂的作用都更强。PPARγ基因敲除细胞对贝沙罗汀的反应减弱，表明PPARγ是贝沙罗汀发挥作用所必需的。这些数据表明，RXR是血管紧张素II介导的血管反应的有效调节剂，部分是通过抑制p38实现的。
