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Ligands Regulate Endothelial Membrane Superoxide Production
1 Division of Pulmonary and Critical Care Medicine, Veterans Affairs and Emory University Medical Centers, Decatur, GA, USA
2 Division of Cardiology, Emory University, Atlanta, GA, USA
* To whom correspondence should be addressed. E-mail: Michael.Hart3{at}med.va.gov.
Recently we demonstrated that the peroxisome proliferator-activated receptor 
(PPAR) ligands, 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 (O2[[rad]]) 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 hours decreased human umbilical vein endothelial cell (HUVEC) membrane NADPH-dependent O2. production detected with ESR 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 by 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 [[rad]]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.
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