Mechanisms of vascular dysfunction in mice with endothelium-specific deletion of the PPAR-δ gene.
Peroxisome proliferator-activated receptor (PPAR)-δ is a nuclear hormone receptor that is mainly involved in lipid metabolism. Recent studies have suggested that PPAR-δ agonists exert vascular protective effects. The present study was designed to characterize vascular function in mice with genetic inactivation of PPAR-δ in the endothelium. Mice with vascular endothelial cell-specific deletion of the PPAR-δ gene (ePPARδ(-/-) mice) were generated using loxP/Cre technology. ePPARδ(-/-) mice were normotensive and did not display any sign of metabolic syndrome. Endothelium-dependent relaxations to ACh and endothelium-independent relaxations to the nitric oxide (NO) donor diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate were both significantly impaired in the aorta and carotid arteries of ePPARδ(-/-) mice (P < 0.05). In ePPARδ(-/-) mouse aortas, phosphorylation of endothelial NO synthase at Ser(1177) was significantly decreased (P < 0.05). However, basal levels of cGMP were unexpectedly increased (P < 0.05). Enzymatic activity of GTP-cyclohydrolase I and tetrahydrobiopterin levels were also enhanced in ePPARδ(-/-) mice (P < 0.05). Most notably, endothelium-specific deletion of the PPAR-δ gene significantly decreased protein expressions of catalase and glutathione peroxidase 1 and resulted in increased levels of H2O2 in the aorta (P < 0.05). In contrast, superoxide anion production was unaltered. Moreover, treatment with catalase prevented the endothelial dysfunction and elevation of cGMP detected in aortas of ePPARδ(-/-) mice. The findings suggest that increased levels of cGMP caused by H2O2 impair vasodilator reactivity to endogenous and exogenous NO. We speculate that chronic elevation of H2O2 predisposes PPAR-δ-deficient arteries to oxidative stress and vascular dysfunction.
Department of Anesthesiology and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota; and.
Livius V
LV
d'Uscio
Tongrong
T
He
Anantha Vijay R
AV
Santhanam
Li-Jung
LJ
Tai
Ronald M
RM
Evans
Zvonimir S
ZS
Katusic
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001011:Aorta / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D017536:Carotid Artery, Common / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D002374:Catalase / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D006136:GTP Cyclohydrolase / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress; D047495:PPAR gamma / Q000172:deficiency* / Q000235:genetics; D010766:Phosphorylation; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D000094765:Glutathione Peroxidase GPX1
D000975:Antioxidants; D047495:PPAR gamma; D014665:Vasodilator Agents; D013481:Superoxides; D001708:Biopterins; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D002374:Catalase; D005979:Glutathione Peroxidase; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D006136:GTP Cyclohydrolase; C003402:sapropterin; D006152:Cyclic GMP; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse
carotid artery; endothelial dysfunction; endothelial nitric oxide synthase; hydrogen peroxide; nitric oxide; peroxisome proliferator-activated receptor-δ; tetrahydrobiopterin