Phospholipid chlorohydrin induces leukocyte adhesion to ApoE-/- mouse arteries via upregulation of P-selectin.
HOCl-modified low-density lipoprotein (LDL) has proinflammatory effects, including induction of inflammatory cytokine production, leukocyte adhesion, and ROS generation, but the components responsible for these effects are not completely understood. HOCl and the myeloperoxidase-H(2)O(2)-halide system can modify both protein and lipid moieties of LDL and react with unsaturated phospholipids to form chlorohydrins. We investigated the proinflammatory effects of 1-stearoyl-2-oleoyl-sn-3-glycerophosphocholine (SOPC) chlorohydrin on artery segments and spleen-derived leukocytes from ApoE(-/-) and C57 Bl/6 mice. Treatment of ApoE(-/-) artery segments with SOPC chlorohydrin, but not unmodified SOPC, caused increased leukocyte-arterial adhesion in a time- and concentration-dependent manner. This could be prevented by pretreatment of the artery with P-selectin or ICAM-1-blocking antibodies, but not anti-VCAM-1 antibody, and immunohistochemistry showed that P-selectin expression was upregulated. However, chlorohydrin treatment of leukocytes did not increase expression of adhesion molecules LFA-1 or PSGL-1, but caused increased release of ROS from PMA-stimulated leukocytes by a CD36-dependent mechanism. The SOPC chlorohydrin-induced adhesion and ROS generation could be abrogated by pretreatment of the ApoE(-/-) mice with pravastatin or a nitrated derivative, NCX 6550. These findings suggest that phospholipid chlorohydrins formed in HOCl-treated LDL could contribute to the proinflammatory effects observed for this modified lipoprotein in vitro.
Dever
Gary J
GJ
Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.
Benson
Robert
R
Wainwright
Cherry L
CL
Kennedy
Simon
S
Spickett
Corinne M
CM
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001057:Apolipoproteins E / Q000235:genetics; D001158:Arteries / Q000187:drug effects / Q000276:immunology; D050197:Atherosclerosis / Q000276:immunology*; D002448:Cell Adhesion / Q000187:drug effects; D002728:Chlorohydrins / Q000378:metabolism* / Q000494:pharmacology; D006997:Hypochlorous Acid / Q000737:chemistry; D007249:Inflammation / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology*; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009566:Nitrates / Q000494:pharmacology; D019007:P-Selectin / Q000032:analysis / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000378:metabolism* / Q000494:pharmacology; D010743:Phospholipids / Q000378:metabolism* / Q000494:pharmacology; D017035:Pravastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation
C516976:1,2,6,7,8,8a-hexahydro-beta,delta,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphthaleneheptanoic acid 4-(nitrooxy)butyl ester; D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D002728:Chlorohydrins; D008077:Lipoproteins, LDL; D009566:Nitrates; D019007:P-Selectin; D010713:Phosphatidylcholines; D010743:Phospholipids; D017382:Reactive Oxygen Species; D018799:Intercellular Adhesion Molecule-1; C027891:1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine; D006997:Hypochlorous Acid; D017035:Pravastatin