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

The attraction, binding, and entry of monocytes into the vessel wall play a n 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 chemota ctic activators. In the present study, we demonstrate th at MM-LDL and oxid ation products of 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine (PA PC) activate endothelial cells to synthesize monocyte chemotactic protein-1 (MCP-1) and interleukin-8 (IL-8). Several lines of evidence suggest that t his activation is mediated by the lipid-dependent transcription factor pero xisome proliferator-activated receptor alpha (PPAR alpha), the most abundan t member of the PPAR family in HAECs. Treatment of transfected CV-1 cells d emonstrated activation of the PPAR alpha ligand-binding domain by MM-LDL, O x-PAPC, or its component phospholipids, 1-palmitoyl-2-oxovalaroyl-sn-glycer o-phosphocholine and 1-palmitoyl-2-glutaroyl-sn-glycero-phosphocholine; the se lipids also activated a consensus peroxisome proliferator-activated rece ptor response element (PPRE) in transfected HAECs. Furthermore, activation of PPAR alpha with synthetic ligand Wy14,643 stimulates the synthesis of IL -8 and MCP-1 by HAECs. By contrast, troglitazone, a PPAR gamma agonist, dec reased the levels of IL-8 and MCP-1. Finally, we demonstrate that unlike wi ld-type endothelial cells, endothelial cells derived from PPARa null mice d o not produce MCP-1/JE in response to Ox-PAPC and MM-LDL. Together, these d ata demonstrate a proinflammatory role for PPAR alpha in mediation of the a ctivation of endothelial cells to produce monocyte chemotactic activity in response to oxidized phospholipids and lipoproteins.