Role for peroxisome proliferator-activated receptor α in oxidized phospholipid-induced synthesis of monocyte chemotactic protein-1 interleukin-8 by endothelial cells

Hans Lee, Weibin Shi, Peter Tontonoz, Shirley Wang, Ganesamoorthy Subbanagounder, Catherine C. Hedrick, Susan Hama, Christine Borromeo, Ronald M. Evans, Judith A. Berliner, Laszlo Nagy

Research output: Contribution to journalArticlepeer-review

Abstract

The attraction, binding, and entry of monocytes into the vessel wall play an important role in atherogenesis. We have previously shown that minimally oxidized/modified LDL (MM-LDL), a pathogenically relevant lipoprotein, can activate human aortic endothelial cells (HAECs) to produce monocyte chemotactic activators. In the present study, we demonstrate that MM-LDL and oxidation products of 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine (PAPC) activate endothelial cells to synthesize monocyte chemotactic protein-1 (MCP-1) and interleukin-8 (IL-8). Several lines of evidence suggest that this activation is mediated by the lipid-dependent transcription factor peroxisome proliferator-activated receptor α (PPARα), the most abundant member of the PPAR family in HAECs. Treatment of transfected CV-1 cells demonstrated activation of the PPARα ligand-binding domain by MM-LDL, Ox-PAPC, or its component phospholipids, 1-palmitoyl-2-oxovalaroyl-sn-glycero-phosphocholine and 1-palmitoyl-2-glutaroyl-sn-glycero-phosphocholine; these lipids also activated a consensus peroxisome proliferator-activated receptor response element (PPRE) in transfected HAECs. Furthermore, activation of PPARα with synthetic ligand Wy14,643 stimulates the synthesis of IL-8 and MCP-1 by HAECs. By contrast, troglitazone, a PPARγ/agonist, decreased the levels of IL-8 and MCP-1. Finally, we demonstrate that unlike wild-type endothelial cells, endothelial cells derived from PPARα null mice do not produce MCP-1/JE in response to Ox-PAPC and MM-LDL. Together, these data demonstrate a proinflammatory role for PPARα in mediation of the activation of endothelial cells to produce monocyte chemotactic activity in response to oxidized phospholipids and lipoproteins.

Original languageEnglish (US)
Pages (from-to)516-521
Number of pages6
JournalCirculation research
Volume87
Issue number6
DOIs
StatePublished - Sep 15 2000
Externally publishedYes

Keywords

  • Atherosclerosis
  • Endothelium
  • Interleukins
  • Lipoproteins
  • Monocyte chemotactic protein-1
  • Phospholipids

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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