Pontsler Aaron V, St Hilaire Andy, Marathe Gopal K, Zimmerman Guy A, McIntyre Thomas M
Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
J Biol Chem. 2002 Apr 12;277(15):13029-36. doi: 10.1074/jbc.M109546200. Epub 2002 Jan 23.
Low density lipoprotein (LDL) oxidation and monocyte infiltration of the vessel wall underlie atherogenesis. These cells express cyclooxygenase-2, but the way oxidized LDL stimulates cyclooxygenase-2 transcription is unknown. Oxidized LDL, oxidatively fragmented phospholipids isolated from oxidized LDL, a synthetic oxidized alkylphospholipid (azPC) that is a potent peroxisome proliferator activated receptor (PPAR) gamma agonist, or the PPARgamma agonist rosiglitazone all induced cyclooxygenase-2 expression and enhanced prostaglandin E(2) (PGE(2)) secretion in primary human monocytes. The cyclooxygenase-2 inhibitor NS398 blocked PPARgamma-induced PGE(2) secretion. Phospholipase A(1) and A(2) digestion shows that oxidized alkylphospholipids, and not oxidized fatty acids, were the relevant agonists. The upstream PPAR-responsive element (PPRE) of cyclooxygenase-2 was required for induction of a luciferase reporter by oxidized phospholipids, azPC, and rosiglitazone, and a (COX-2 PPRE)(3)-luciferase reporter was responsive to these PPARgamma agonists. Circulating human monocytes do not contain PPARgamma, but PPARgamma was induced rapidly (<4 h) in monocytes upon ligation of surface ICAM-3, but not P-selectin glycoprotein-1 even though both interactions prime cytokine secretion. Cyclooxygenase-2 induction by oxidized phospholipids only occurred in monocytes containing PPARgamma. Thus PPARgamma was induced rapidly in primary monocytes by appropriate outside-in signaling, sensitizing them to previously undetectable agonists in oxidized LDL. Cyclooxygenase-2 and PGE(2) secretion are induced, not inhibited, by selective PPARgamma agonists that include oxidatively fragmented phospholipids in oxidized LDL.
低密度脂蛋白（LDL）氧化和单核细胞浸润血管壁是动脉粥样硬化发生的基础。这些细胞表达环氧化酶-2，但氧化型LDL刺激环氧化酶-2转录的方式尚不清楚。氧化型LDL、从氧化型LDL中分离出的氧化断裂磷脂、一种作为强力过氧化物酶体增殖物激活受体（PPAR）γ激动剂的合成氧化烷基磷脂（azPC）或PPARγ激动剂罗格列酮，均能诱导原代人单核细胞中环氧化酶-2的表达，并增强前列腺素E2（PGE2）的分泌。环氧化酶-2抑制剂NS398可阻断PPARγ诱导的PGE2分泌。磷脂酶A1和A2消化表明，相关激动剂是氧化烷基磷脂，而非氧化脂肪酸。环氧化酶-2的上游PPAR反应元件（PPRE）是氧化磷脂、azPC和罗格列酮诱导荧光素酶报告基因所必需的，且（COX-2 PPRE）3荧光素酶报告基因对这些PPARγ激动剂有反应。循环中的人单核细胞不含PPARγ，但在表面ICAM-3被连接后，单核细胞中PPARγ会迅速（<4小时）被诱导，而P-选择素糖蛋白-1连接时则不会，尽管这两种相互作用均能引发细胞因子分泌。氧化磷脂诱导环氧化酶-2仅发生在含有PPARγ的单核细胞中。因此，通过适当的外向内信号传导，原代单核细胞中PPARγ会迅速被诱导，使其对氧化型LDL中先前无法检测到的激动剂敏感。包括氧化型LDL中的氧化断裂磷脂在内的选择性PPARγ激动剂可诱导而非抑制环氧化酶-2和PGE2的分泌。
