title: Lipoprotein-derived lysophosphatidic acid promotes atherosclerosis by releasing CXCL1 from the endothelium.
abstract: 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.
authors.affiliation: Institute for Molecular Cardiovascular Research, RWTH Aachen University, Germany.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhou
authors.forename: Pallavi
authors.initials: P
authors.lastname: Subramanian
authors.forename: Gueler
authors.initials: G
authors.lastname: Sevilmis
authors.forename: Brigitta
authors.initials: B
authors.lastname: Globke
authors.forename: Oliver
authors.initials: O
authors.lastname: Soehnlein
authors.forename: Ela
authors.initials: E
authors.lastname: Karshovska
authors.forename: Remco
authors.initials: R
authors.lastname: Megens
authors.forename: Kathrin
authors.initials: K
authors.lastname: Heyll
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.forename: Jean Sébastien
authors.initials: JS
authors.lastname: Saulnier-Blache
authors.forename: Markus
authors.initials: M
authors.lastname: Reinholz
authors.forename: Marc
authors.initials: M
authors.lastname: van Zandvoort
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.forename: Andreas
authors.initials: A
authors.lastname: Schober
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology; D050197:Atherosclerosis / Q000139:chemically induced* / Q000378:metabolism*; D002339:Carotid Arteries / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000378:metabolism*; D004036:Diet, Atherogenic; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006949:Hyperlipidemias; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008246:Lysophospholipids / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D008077:Lipoproteins, LDL; D008246:Lysophospholipids; D034741:RNA, Small Interfering; D049368:Receptors, Lysophosphatidic Acid; C032881:lysophosphatidic acid