Peroxisome proliferator-activated receptor-gamma ligands regulate endothelial membrane superoxide production |
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Authors: | Hwang Jinah Kleinhenz Dean J Lassègue Bernard Griendling Kathy K Dikalov Sergey Hart C Michael |
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Institution: | Division of Pulmonary and Critical Care Medicine, Pulmonary Section, Atlanta Veterans Affairs and Emory University Medical Centers (151-P) 1670 Clairmont Road, Decatur, GA 30033, USA. |
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Abstract: | Recently, we demonstrated that the peroxisome proliferator-activated receptor- (PPAR-) ligands, either 15-deoxy-12,14-prostaglandin J2 (15d-PGJ2) or ciglitazone, increased endothelial nitric oxide (·NO) release without altering endothelial nitric oxide synthase (eNOS) expression (4). However, the precise molecular mechanisms of PPAR--stimulated endothelial·NO release remain to be defined. Superoxide anion radical (O2·) combines with ·NO to decrease·NO bioavailability. NADPH oxidase, which produces O2·, and Cu/Zn-superoxide dismutase (Cu/Zn-SOD), which degrades O2·, thereby contribute to regulation of endothelial cell·NO metabolism. Therefore, we examined the ability of PPAR- ligands to modulate endothelial O2· metabolism through alterations in the expression and activity of NADPH oxidase or Cu/Zn-SOD. Treatment with 10 µM 15d-PGJ2 or ciglitazone for 24 h decreased human umbilical vein endothelial cell (HUVEC) membrane NADPH-dependent O2· production detected with electron spin resonance spectroscopy. Treatment with 15d-PGJ2 or ciglitazone also reduced relative mRNA levels of the NADPH oxidase subunits, nox-1, gp91phox (nox-2), and nox-4, as measured using real-time PCR analysis. Concordantly, Western blot analysis demonstrated that 15d-PGJ2 or ciglitazone decreased nox-2 and nox-4 protein expression. PPAR- ligands also stimulated both activity and expression of Cu/Zn-SOD in HUVEC. These data suggest that in addition to any direct effects on endothelial·NO production, PPAR- ligands enhance endothelial·NO bioavailability, in part by altering endothelial O2· metabolism through suppression of NADPH oxidase and induction of Cu/Zn-SOD. These findings further elucidate the molecular mechanisms by which PPAR- ligands directly alter vascular endothelial function. reduced nicotinamide adenine dinucleotide phosphate oxidase; copper/zinc superoxide dismutase; nitric oxide; endothelial cells |
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