Overexpression of retinoid X receptor beta provides protection against oxidized low-density lipoprotein-induced inflammation via regulating PGC1α-dependent mitochondrial homeostasis in endothelial cells

Biochem Pharmacol. 2021 Jun;188:114559. doi: 10.1016/j.bcp.2021.114559. Epub 2021 Apr 17.

Abstract

Retinoid X receptor beta (RXRβ) has been poorly studied in atherosclerosis. The aim of the present study is to explore the function of RXRβ in oxidized low density lipoprotein (ox-LDL)-induced inflammation in endothelial cells and the underlying mechanism. The protein expression of RXRβ in the aorta of atherosclerotic mice was detected. A lentivirus vector for RXRβ overexpression and RNA interference for RXRβ downregulation were constructed and transfected into human aortic endothelial cells (HAECs). The results showed that RXRβ protein expression was downregulated in aorta of high fat diet (HFD)-fed LDLr-/- mice and ox-LDL-treated HAECs. The ox-LDL-induced production of pro-inflammatory cytokines and activations of TLR9/NF-κB and NLRP3/caspase-1 inflammasome pathway were significantly decreased by RXRβ overexpression but increased by RXRβ knockdown in HAECs. The ox‑LDL‑induced mitochondrial damage indicated as the increased generation of mitochondrial ROS, decreased mitochondrial membrane potential and increased mitochondrial DNA release was abolished by RXRβ overexpression but aggravated by RXRβ knockdown. Treatment with mito-TEMPO significantly reduced the increased production of pro-inflammatory cytokines and activations of TLR9/NF-κB and NLRP3/caspase-1 inflammasome induced by RXRβ knockdown in ox-LDL treated HAECs. Moreover, peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α) protein expression was reduced in HFD-fed LDLr-/- mice. RXRβ could interact with PGC1α in HAECs. Ox-LDL-induced reduction of PGC1α was significantly inhibited by RXRβ overexpression and aggravated by RXRβ downregulation. Our further study showed that transfection of PGC1α siRNA abrogated the alleviative effects of RXRβ overexpression on mitochondrial damage and inflammation in ox-LDL treated cells. The present study indicates that RXRβ exerted protective effects against the ox-LDL-induced inflammation may through regulating PGC1α-dependent mitochondrial homeostasis.

Keywords: Endothelial cells; Oxidized low-density lipoprotein; PGC1α; Retinoid X receptor beta.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • DNA-Binding Proteins / biosynthesis*
  • DNA-Binding Proteins / genetics
  • Diet, High-Fat / adverse effects
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Gene Expression Regulation
  • Homeostasis / drug effects
  • Homeostasis / physiology
  • Humans
  • Inflammation Mediators / antagonists & inhibitors
  • Inflammation Mediators / metabolism*
  • Lipoproteins, LDL / toxicity*
  • Male
  • Mice
  • Mice, Knockout
  • Mitochondria / drug effects
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / biosynthesis*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics

Substances

  • DNA-Binding Proteins
  • Inflammation Mediators
  • Lipoproteins, LDL
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Rxrb protein, mouse
  • oxidized low density lipoprotein