title: PPARδ activation protects endothelial function in diabetic mice.
abstract: Recent evidence highlights the therapeutic potential of peroxisome proliferator-activated receptor-δ (PPARδ) agonists to increase insulin sensitivity in diabetes. However, the role of PPARδ in regulating vascular function is incompletely characterized. We investigate whether PPARδ activation improves endothelial function in diabetic and obese mice. PPARδ knockout (KO) and wild-type (WT) mice fed with high-fat diet and db/db mice were used as diabetic mouse models, compared with PPARδ KO and WT mice on normal diet and db/m(+) mice. Endothelium-dependent relaxation (EDR) was measured by wire myograph. Flow-mediated vasodilatation (FMD) was measured by pressure myograph. Nitric oxide (NO) production was examined in primary endothelial cells from mouse aortae. PPARδ agonist GW1516 restored EDRs in mouse aortae under high-glucose conditions or in db/db mouse aortae ex vivo. After oral treatment with GW1516, EDRs in aortae and FMDs in mesenteric resistance arteries were improved in obese mice in a PPARδ-specific manner. The effects of GW1516 on endothelial function were mediated through phosphatidylinositol 3-kinase (PI3K) and Akt with a subsequent increase of endothelial nitric oxide synthase (eNOS) activity and NO production. The current study demonstrates an endothelial-protective effect of PPARδ agonists in diabetic mice through PI3K/Akt/eNOS signaling, suggesting the therapeutic potential of PPARδ agonists for diabetic vasculopathy.
authors.affiliation: Institute of Vascular Medicine, Li Ka Shing Institute of Health Sciences, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Xiao Yu
authors.initials: XY
authors.lastname: Tian
authors.forename: Wing Tak
authors.initials: WT
authors.lastname: Wong
authors.forename: Nanping
authors.initials: N
authors.lastname: Wang
authors.forename: Ye
authors.initials: Y
authors.lastname: Lu
authors.forename: Wai San
authors.initials: WS
authors.lastname: Cheang
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Limei
authors.initials: L
authors.lastname: Liu
authors.forename: Yahan
authors.initials: Y
authors.lastname: Liu
authors.forename: Susanna Sau-Tuen
authors.initials: SS
authors.lastname: Lee
authors.forename: Zhen Yu
authors.initials: ZY
authors.lastname: Chen
authors.forename: John P
authors.initials: JP
authors.lastname: Cooke
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Yao
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D059305:Diet, High-Fat / Q000009:adverse effects; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D047494:PPAR delta / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013844:Thiazoles / Q000627:therapeutic use*
chemical_list: C425931:GW 501516; D047494:PPAR delta; D013844:Thiazoles; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt