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Endothelium-dependent Vasodilator Effects of Peroxisome Proliferator-Activated Receptor Beta Agonists via the phosphatidyl-inositol-3 kinase-Akt Pathway

Endothelium-dependent Vasodilator Effects of Peroxisome Proliferator-Activated Receptor Beta Agonists via the phosphatidyl-inositol-3 kinase-Akt Pathway

Rosario Jiménez, Manuel Sánchez, María José Zarzuelo, Miguel Romero, Ana María Quintela, Rocío López-Sepúlveda, Pilar Galindo, Manuel Gómez-Guzmán, Jose Manuel Haro, Antonio Zarzuelo, Francisco Pérez-Vizcaíno, etc.

J Pharmacol Exp Ther. 2010 Feb;332(2):554-61.

PMID: 19906781

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP869896764	2,2′-Bis[4-(trifluoromethyl)phenyl]-5,5′-bithiazole		869896-76-4	Price

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