Department of Pharmacology, School of Pharmacy, University of Granada, Granada, Spain.
J Pharmacol Exp Ther. 2010 Feb;332(2):554-61. doi: 10.1124/jpet.109.159806. Epub 2009 Nov 11.
Peroxisome proliferator-activated receptor beta/delta (PPAR-beta) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily that regulates the transcription of many target genes. More recently, acute, nongenomic effects of PPAR-beta agonists have also been described. In the present study, we hypothesized that PPAR-beta agonists might exert acute nongenomic effects on vascular tone. Here, we report that the structurally unrelated PPAR-beta ligands [4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]phenoxy]acetic acid (L-165041) and 4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl] methyl]thio]-2-methylphenoxy]acetic acid (GW0742) induced vascular relaxation in phenylephrine-precontracted endothelium-intact rat aortic rings, which was significantly inhibited by endothelial denudation or nitric-oxide synthase (NOS) inhibition with N(G)-nitro-l-arginine methylester. These relaxant effects reached steady state within 15 min. The relaxation induced by L-165041 and GW0742 in aortic rings precontracted with the thromboxane A(2) analog 9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F2alpha (U-46619) was unaffected either by removal of extracellular calcium or by incubation with calcium-free solution containing the intracellular calcium chelator 1,2-bis-(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester. However, the phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY-294002) inhibited the endothelium-dependent relaxant responses induced by both PPAR-beta agonists. Blockade of PPAR-beta with 3-[[[2-methoxy-4-(phenylamino)phenyl]amino]sulfonyl]-2-thiophenecarboxylic acid methyl ester (GSK0660) also partially inhibited these relaxant responses, although PPAR-gamma blockade with 2-chloro-5-nitro-N-phenylbenzamide (GW9662) had no effect. In human umbilical vein endothelial cells, L-165041 and GW0742 increased nitric oxide (NO) production and Akt and endothelial NOS (eNOS) phosphorylation, which were sensitive to PI3K inhibition and PPAR-beta blockade. In conclusion, the PPAR-beta agonists acutely caused vasodilatation, which was partially dependent on endothelial-derived NO. The eNOS activation is calcium-independent and seems to be related to activation of the PI3K-Akt-eNOS pathway.
过氧化物酶体增殖物激活受体 β/δ（PPAR-β）是一种配体激活的转录因子，属于核激素受体超家族，可调节许多靶基因的转录。最近，也描述了 PPAR-β激动剂的急性非基因组效应。在本研究中，我们假设 PPAR-β激动剂可能对血管张力产生急性非基因组效应。在这里，我们报告结构上不相关的 PPAR-β配体[4-[3-(4-乙酰基-3-羟基-2-丙基苯氧基)丙氧基]苯氧基]乙酸（L-165041）和 4-[[[2-[3-氟-4-（三氟甲基）苯基]-4-甲基-5-噻唑基]甲基]硫代]-2-甲基苯氧基]乙酸（GW0742）可诱导去内皮完整的预先收缩的苯肾上腺素预收缩的大鼠主动脉环松弛，内皮剥脱或用 N(G)-硝基-L-精氨酸甲酯抑制一氧化氮合酶（NOS）可显著抑制这种松弛作用。这些松弛作用在 15 分钟内达到稳定状态。L-165041 和 GW0742 诱导预先收缩的血栓烷 A2 类似物 9,11-去氧-11α，9α-环氧甲酰基前列腺素 F2α（U-46619）的血管舒张作用不受去除细胞外钙或用含有细胞内钙螯合剂 1,2-双（邻氨基苯氧基）乙胺-N，N，N'，N'-四乙酸四（乙酰氧甲基）酯的无钙溶液孵育的影响。然而，磷脂酰肌醇 3-激酶（PI3K）抑制剂 2-（4-吗啉基）-8-苯基-1（4H）-苯并吡喃-4-酮盐酸盐（LY-294002）抑制了两种 PPAR-β激动剂诱导的内皮依赖性舒张反应。用 3-[[[2-甲氧基-4-（苯氨基）苯基]氨基]磺酰基]-2-噻吩羧酸甲酯（GSK0660）阻断 PPAR-β也部分抑制了这些舒张反应，尽管用 2-氯-5-硝基-N-苯基苯甲酰胺（GW9662）阻断 PPAR-γ没有影响。在人脐静脉内皮细胞中，L-165041 和 GW0742 增加了一氧化氮（NO）的产生和 Akt 和内皮型一氧化氮合酶（eNOS）的磷酸化，这些反应对 PI3K 抑制和 PPAR-β 阻断敏感。总之，PPAR-β激动剂可引起急性血管舒张，这部分依赖于内皮衍生的 NO。eNOS 的激活与钙无关，似乎与 PI3K-Akt-eNOS 途径的激活有关。
