PPARγ ligands induce prostaglandin production in vascular smooth muscle cells:: indomethacin acts as a peroxisome proliferator-activated receptor-γ antagonist
PPARγ ligands induce prostaglandin production in vascular smooth muscle cells:: indomethacin acts as a peroxisome proliferator-activated receptor-γ antagonist
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DOI：
10.1096/fj.02-1075fje
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发表时间：
2003-08-01
期刊：
影响因子：
4.8
通讯作者：
Warner, TD
中科院分区：
文献类型：
--
作者：
Bishop-Bailey, D;Warner, TD
过氧化物酶体增殖物激活受体（PPAR）γ和诱导型环氧合酶-2（考克斯-2）在动脉粥样硬化病变中表达，特别是在内膜单核细胞和血管平滑肌细胞中。因此，我们研究了PPAR之间的相互作用。和诱导型环氧合酶（考克斯-2）的表达。合成的PPARgamma配体罗格列酮诱导RASMC释放前列腺素（PG），包括PGD（2），PGD是假定的内源性PPARgamma配体15-脱氧-Delta（12，14）-前列腺素J（2）的前体。此外，罗格列酮与IL-1 β协同作用，进一步诱导前列腺素释放，并影响磷脂酶A（2）和考克斯-2的表达。罗格列酮诱导的前列腺素释放被PPARgamma部分激动剂GW 0072和PPARgamma拮抗剂GW 9662抑制。罗格列酮还可诱导RASMC凋亡，这种作用不能解释为诱导的前列腺素类的自分泌效应，而是对花生四烯酸释放的作用，因为细胞死亡不受非选择性考克斯抑制剂吡罗昔康或选择性考克斯-2抑制剂DFP的影响，但受分泌型或胞质型磷脂酶A抑制剂的影响（2）。相比之下，吲哚美辛，一种环氧化酶活性的替代抑制剂，抑制罗格列酮诱导的细胞死亡，和罗格列酮诱导的PPAR报告基因激活。
Peroxisome proliferator-activated receptor (PPAR)gamma and inducible cyclooxygenase-2 (COX-2) are expressed in atherosclerotic lesions, particularly in the intimal monocytic and vascular smooth muscle cells. We have therefore studied the interaction between PPAR. and inducible cyclo-oxygenase (COX-2) in rat aortic vascular smooth muscle cells (RASMC)s. The synthetic PPARgamma ligand rosiglitazone induced prostaglandin (PG) release from RASMCs, including that of PGD(2), the precursor of the putative endogenous PPARgamma ligand 15-deoxy-Delta(12,14)-prostaglandin J(2). Moreover, rosiglitazone both synergized with IL-1beta to further induce prostaglandin release and affected the expression of phospholipase A(2) and COX-2. Rosiglitazone-induced prostaglandin release was inhibited by the PPARgamma partial agonist GW0072 and the PPARgamma antagonist GW9662. Rosiglitazone also induced RASMC apoptosis, an effect not explained as an autocrine effect of the induced-prostanoids, but on arachidonic acid release, as cell death was unaffected by either the nonselective COX inhibitor piroxicam or the selective COX-2 inhibitor DFP, but by inhibitors of either secretory or cytosolic phospholipase A(2). In contrast, indomethacin, an alternative inhibitor of cyclooxygenase activity, inhibited both rosiglitazone-induced cell death, and rosiglitazone-induced PPAR reporter gene activation.