Lipoprotein-Derived Lysophosphatidic Acid Promotes Atherosclerosis by Releasing CXCL1 from the Endothelium

• Published in: Cell metabolism 2011-05, Vol.13 (5), p.592-600
• Main Authors: Zhou, Zhe, Subramanian, Pallavi, Sevilmis, Gueler, Globke, Brigitta, Soehnlein, Oliver, Karshovska, Ela, Megens, Remco, Heyll, Kathrin, Chun, Jerold, Saulnier-Blache, Jean Sébastien, Reinholz, Markus, van Zandvoort, Marc, Weber, Christian, Schober, Andreas
• Format: Article
• Language: English
• Subjects: Animals; Apolipoproteins E - physiology; Atherosclerosis - chemically induced; Atherosclerosis - metabolism; Carotid Arteries - cytology; Carotid Arteries - drug effects; Carotid Arteries - metabolism; Cells, Cultured; Chemokine CXCL1 - metabolism; Diet, Atherogenic; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Hyperlipidemias; Lipoproteins, LDL - metabolism; Lysophospholipids - pharmacology; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes - cytology; Monocytes - drug effects; Monocytes - metabolism; Receptors, Lysophosphatidic Acid - antagonists & inhibitors; Receptors, Lysophosphatidic Acid - genetics; Receptors, Lysophosphatidic Acid - metabolism; RNA, Small Interfering - genetics
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2011.02.016

Oxidatively modified low-density lipoprotein (oxLDL) plays a key role in the initiation of atherosclerosis by increasing monocyte adhesion. The mechanism that is responsible for the oxLDL-induced atherogenic monocyte recruitment in vivo, however, still remains unknown. Oxidation of LDL generates lysophosphatidylcholine, which is the main substrate for the lysophosphatidic acid (LPA) generating enzyme autotaxin. We show that oxLDL requires endothelial LPA receptors and autotaxin to elicit CXCL1-dependent arterial monocyte adhesion. Unsaturated LPA releases endothelial CXCL1, which is subsequently immobilized on the cell surface and mediates LPA-induced monocyte adhesion. Local and systemic application of LPA accelerates the progression of atherosclerosis in mice. Blocking the LPA receptors LPA 1 and LPA 3 reduced hyperlipidemia-induced arterial leukocyte arrest and atherosclerosis in the presence of functional CXCL1. Thus, atherogenic monocyte recruitment mediated by hyperlipidemia and modified LDL crucially depends on LPA, which triggers endothelial deposition of CXCL1, revealing LPA signaling as a target for cardiovascular disease treatments. [Display omitted] ► Modified LDL-induced monocyte adhesion via CXCL1 requires endothelial LPA receptors ► Unsaturated LPA promotes CXCL1-dependent monocyte adhesion and atherogenesis ► Hyperlipidemia enhances monocyte recruitment via the LPA 1 and LPA 3 receptors ► Blocking LPA 1 and LPA 3 impairs atherosclerosis and lesional macrophage accumulation