Activation of TRPV1 Prevents OxLDL-Induced Lipid Accumulation and TNF-α-Induced Inflammation in Macrophages: Role of Liver X Receptorα

Jin-Feng Zhao,Tzong-Shyuan Lee,Li-Chieh Ching,Yu Ru Kou,Shing-Jong Lin,Song-Kun Shyue,Jeng Wei

doi:10.1155/2013/925171

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 (Ca2+) 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 LXRα siRNA in macrophages. Our data suggest that LXRα plays a pivotal role in TRPV1-activation-conferred protection against oxLDL-induced lipid accumulation and TNF-α-induced inflammation in macrophages.

Highlights

Complications of atherosclerosis are the leading cause of death in Western society
Because neuronal TRPV1 can be activated by several oxidative stimuli and lipids [14, 18, 19, 24], we examined the effect of oxidized low-density lipoprotein (LDL) (oxLDL) on the expression of TRPV1 in macrophages
Treating Bone-marrow-derived macrophages (BMDMs) with 50 μg/mL oxLDL for up to 24 h time-dependently increased the expression of TRPV1 (Figure 1(c)) as early as 3 h after treatment or up to 24 h

Summary

Introduction

Atherosclerosis starts with increased circulating cholesterol levels and involves several events leading to chronic vascular inflammation [1, 2]. The initiation and progression of atherosclerosis largely depend on the function of macrophage foam cells, which focally accumulate within the artery wall and release various cytokines and chemokines to induce inflammation [2,3,4]. The formation of foam cells primarily results from uncontrolled uptake of modified low-density lipoprotein (LDL) by macrophages, which leads to excess lipoprotein-derived lipid accumulation inside cells and induction of proinflammatory mediators [3, 4]. Cellular lipid levels of foam cells are dynamically regulated by macrophage scavenger receptors (SRs) and cholesterol efflux transporters. Growing evidence indicates that preventing the formation of foam cells can impede the progression of atherosclerosis [11,12,13], but much remains to be explored

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