Mechanisms of vascular dysfunction in mice with endothelium-specific deletion of the PPAR-δ gene

Abstract

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.

Role of prostacyclin signaling in endothelial production of soluble amyloid precursor protein-α in cerebral microvessels

“…32 Here we confirmed that PPARd was knockeddown in the endothelium of cerebral microvessels derived from ePPARd À/À mice. In cultured cerebral microvascular endothelial cells of ePPARd À/À mice PPARd mRNA was deleted (Suppl.…”

“…32 Relaxations to cicaprost were obtained in aortas of wild-type and IP À/À mice during submaximal contractions to phenylephrine.…”

“…Primers for mouse PPARd, eNOS, and GAPDH were used as described in our previous publication. 32 Knockdown of PPAR and SIRT1 by small interfering RNA (siRNA) Experiments were performed as described in our previous studies by use of Lipofectamine 2000 (Invitrogen). 39 PPARd-siRNA targeting human PPARd mRNA (ON-TARGETplus SMART pool), and Control-siRNA (ON-TARGETplus Non-targeting siRNA#1) were obtained from Dharmacon (Lafayette, CO).…”

“…30 Prior studies suggest that systemic activation of PPARd is protective against major cardiovascular risk factors including dyslipidemia, insulin resistance, and obesity. 30 In peripheral blood vessels, pharmacological analysis demonstrated that PPARd agonists exert vascular protective effects 13,31,32 ; however, the role of PPARd in cerebral vascular function is not fully understood. In our previous study we demonstrated that in the cerebral microvessels, activation of PPARd prevented endothelial dysfunction thereby suggesting that endothelial PPARd might be an important vasoprotective molecule.…”

Oleanolic acid ameliorates high glucose-induced endothelial dysfunction via PPARδ activation

“…2). In endothelium-specific PPARδ deficient mice, both endothelium-dependent relaxations to ACh and endothelium independent relaxations to the NO donor were significantly impaired in the arteries, accompanied by decreased eNOS-Ser 1177 phosphorylation34. It is suggested that OA restores HG-impaired endothelial function by a PPARδ-mediated activation of Akt/eNOS signaling pathways.…”