title: Activation of TRPV1 prevents OxLDL-induced lipid accumulation and TNF-α-induced inflammation in macrophages: role of liver X receptor α.
abstract: The transient receptor potential vanilloid type 1 (TRPV1) is crucial in the pathogenesis of atherosclerosis; yet its role and underlying mechanism in the formation of macrophage foam cells remain unclear. Here, we show increased TRPV1 expression in the area of foamy macrophages in atherosclerotic aortas of apolipoprotein E-deficient mice. Exposure of mouse bone-marrow-derived macrophages to oxidized low-density lipoprotein (oxLDL) upregulated the expression of TRPV1. In addition, oxLDL activated TRPV1 and elicited calcium (Ca(2+)) influx, which were abrogated by the pharmacological TRPV1 antagonist capsazepine. Furthermore, oxLDL-induced lipid accumulation in macrophages was ameliorated by TRPV1 agonists but exacerbated by TRPV1 antagonist. Treatment with TRPV1 agonists did not affect the internalization of oxLDL but promoted cholesterol efflux by upregulating the efflux ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. Moreover, the upregulation of ABC transporters was mainly through liver X receptor α-(LXRα-) dependent regulation of transcription. Moreover, the TNF-α-induced inflammatory response was alleviated by TRPV1 agonists but aggravated by the TRPV1 antagonist and LXR α siRNA in macrophages. Our data suggest that LXR α plays a pivotal role in TRPV1-activation-conferred protection against oxLDL-induced lipid accumulation and TNF-α-induced inflammation in macrophages.
authors.affiliation: Department of Physiology, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Jin-Feng
authors.initials: JF
authors.lastname: Zhao
authors.forename: Li-Chieh
authors.initials: LC
authors.lastname: Ching
authors.forename: Yu Ru
authors.initials: YR
authors.lastname: Kou
authors.forename: Shing-Jong
authors.initials: SJ
authors.lastname: Lin
authors.forename: Jeng
authors.initials: J
authors.lastname: Wei
authors.forename: Song-Kun
authors.initials: SK
authors.lastname: Shyue
authors.forename: Tzong-Shyuan
authors.initials: TS
authors.lastname: Lee
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D050916:TRPV Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D034741:RNA, Small Interfering; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; C071423:capsazepine; D002211:Capsaicin; D002118:Calcium