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Disruption of endothelial peroxisome proliferator-activated receptor- reduces vascular nitric oxide production

Departments of ¹Medicine, ²Pathology, and ³Pediatrics, Atlanta Veterans Affairs and Emory University Medical Centers, Atlanta, Georgia

Submitted February 11, 2009 ; accepted in final form August 3, 2009

Vascular endothelial cells express the ligand-activated transcription factor, peroxisome proliferator-activated receptor- (PPAR), which participates in the regulation of metabolism, cell proliferation, and inflammation. PPAR ligands attenuate, whereas the loss of function mutations in PPAR stimulate, endothelial dysfunction, suggesting that PPAR may regulate vascular endothelial nitric oxide production. To explore the role of endothelial PPAR in the regulation of vascular nitric oxide production in vivo, mice expressing Cre recombinase driven by an endothelial-specific promoter were crossed with mice carrying a floxed PPAR gene to produce endothelial PPAR null mice (ePPAR^–/–). When compared with littermate controls, ePPAR^–/– animals were hypertensive at baseline and demonstrated comparable increases in systolic blood pressure in response to angiotensin II infusion. When compared with those of control animals, aortic ring relaxation responses to acetylcholine were impaired, whereas relaxation responses to sodium nitroprusside were unaffected in ePPAR^–/– mice. Similarly, intact aortic segments from ePPAR^–/– mice released less nitric oxide than those from controls, whereas endothelial nitric oxide synthase expression was similar in control and ePPAR^–/– aortas. Reduced nitric oxide production in ePPAR^–/– aortas was associated with an increase in the parameters of oxidative stress in the blood and the activation of nuclear factor-B in aortic homogenates. These findings demonstrate that endothelial PPAR regulates vascular nitric oxide production and that the disruption of endothelial PPAR contributes to endothelial dysfunction in vivo.

endothelial nitric oxide synthase

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