Liver X Receptor Activator Downregulates Angiotensin II Type 1 Receptor Expression Through Dephosphorylation of Sp1

Abstract

Abstract-Atherosclerosis is considered to be a combined disorder of lipid metabolism and chronic inflammation. Recent studies have reported that liver X receptors (LXRs) are involved in lipid metabolism and inflammation and that LXR agonists inhibit atherogenesis. In contrast, angiotensin II is well known to accelerate atherogenesis through activation of the angiotensin II type 1 receptor (AT1R). To better understand the mechanism of LXR on the prevention of atherogenesis, we examined whether activation of LXR affects AT1R expression in vascular smooth muscle cells. T0901317, a synthetic LXR ligand, decreased AT1R mRNA and protein expression with a peak reduction at 6 hours and 12 hours of incubation, respectively. A well-established ligand of LXR, 22-(R)-hydroxycholesterol, also suppressed AT1R expression. The downregulation of AT1R by T0901317 required de novo protein synthesis. AT1R gene promoter activity measured by luciferase assay revealed that the DNA segment between Ϫ61 bp and ϩ25 bp was sufficient for downregulation. Luciferase construct with a mutation in Sp1 binding site located in this segment lost its response to T0901317. T0901317 decreased Sp1 serine phosphorylation. Although preincubation of vascular smooth muscle cells with T0901317 for 30 minutes had no effect on angiotensin II-induced extracellular signal-regulated kinase phosphorylation, phosphorylation of extracellular signal-regulated kinase by angiotensin II was markedly suppressed after 6 hours of preincubation. These results indicate that the suppression of AT1R may be one of the important mechanisms by which LXR ligands exert antiatherogenic effects. T he liver X receptors (LXRs) are member of the nuclear hormone receptor superfamily. 1 Their endogenous ligands are oxidized cholesterol derivatives, such as oxysterols 1 and glucose. 2 LXRs regulate the expression of genes involved in lipid and glucose metabolism. In lipid metabolism, LXRs are known to regulate genes involved in "reverse cholesterol transport," which includes cholesterol efflux, transport, and excretion. ATP binding cassette A1 is involved in cholesterol efflux, and ABCG5 and ABCG8 are involved in cholesterol transport. 3,4 Expression of these ABC proteins is increased by LXR agonists. In mice, LXR agonists were reported to promote biliary and fecal excretion of cholesterol. 5 It was reported recently that glucose directly activated LXRs 2 and regulated the transcription of genes such as GLUT4. 6 In addition, LXR agonists were reported to negatively regulate the expression of inflammatory cytokines 7 and prevent the formation of atherosclerotic lesions in atherosclerosis-prone mice. 8,9 The effects of angiotensin II (Ang II) are mediated by Ang II receptors, and so far 2 isoforms, type 1 receptor (AT1R) and type 2 receptor, have been identified. 10 AT1R mediates most of the traditional effects of Ang II, such as vasoconstriction and cell proliferation. It is well known that Ang II enhances atherogenesis, 11,12 and an AT1R antagonist attenuated atherogenesis in animal mode...

Activation of liver X receptor-α reduces activation of the renal and cardiac renin–angiotensin–aldosterone system

“…The transcriptional regulation of ACE is largely unknown, whereas regulation of AT 1 R is tight, complex and well described. 14 Our findings of decreased renal AT 1 R mRNA expression are in line with those of Imayama et al, 15 who demonstrated LXR to be a negative regulator of AT 1 R in cultured vascular smooth muscle cells. On the other hand, Leik et al showed that LXR activation by GW3965 leads to a transient increase in vascular gene expression of the AT 1 R, which decreased over time (measured over an 8-h period).…”

Activation of LXRα improves cardiac remodeling induced by pulmonary artery hypertension in rats

“…Thus, we assume that the TLR-4 pathway may not be involved in LXR-mediated inflammatory pathways. In addition, although AT1 is inhibited by LXR activation in smooth muscle 31 , we did not observe any significant difference in AT1 expression in PAH cardiocytes. Similar results were noted in our previous in vitro experiment.…”

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

“…For instance, activation of PPARg by rosiglitazone has been shown to decrease AIIinduced SMC hypertrophy (Benkirane et al, 2006). In contrast, PPARd agonists decrease SMC senescence associated with AII (Kim et al, 2011), and LXR agonists decrease expression of the AT 1 R receptor (Imayama et al, 2008). The effects of rexinoids on SMCs have not been studied; however, in endothelial cells, bexarotene inhibits tumor necrosis factor a-induced adhesion molecule expression and decreases mononuclear cell recruitment (Sanz et al, 2012).…”