Endothelium-dependent vasodilator effects of peroxisome proliferator-activated receptor beta agonists via the phosphatidyl-inositol-3 kinase-Akt pathway.
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.
Jiménez
Rosario
R
Department of Pharmacology, School of Pharmacy, University of Granada, Granada, Spain.
Sánchez
Manuel
M
Zarzuelo
María José
MJ
Romero
Miguel
M
Quintela
Ana María
AM
López-Sepúlveda
Rocío
R
Galindo
Pilar
P
Gómez-Guzmán
Manuel
M
Haro
Jose Manuel
JM
Zarzuelo
Antonio
A
Pérez-Vizcaíno
Francisco
F
Duarte
Juan
J
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D048068:PPAR-beta / Q000819:agonists*; D010642:Phenoxyacetates / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013450:Sulfones / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014471:Umbilical Veins / Q000187:drug effects / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*; D010636:Phenols; D013438:Sulfhydryl Compounds
D000813:Anilides; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D048068:PPAR-beta; D010642:Phenoxyacetates; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D013450:Sulfones; D013844:Thiazoles; D013876:Thiophenes; C457499:2-chloro-5-nitrobenzanilide; C520164:4-(3-(2-propyl-3-hydroxy-4-acetyl)phenoxy)propyloxyphenoxy acetic acid; C529769:GSK0660; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds