title: PPARδ Is Required for Exercise to Attenuate Endoplasmic Reticulum Stress and Endothelial Dysfunction in Diabetic Mice.
abstract: Physical activity has profound benefits on health, especially on cardiometabolic wellness. Experiments in rodents with trained exercise have shown that exercise improves vascular function and reduces vascular inflammation by modulating the balance between nitric oxide (NO) and oxidative stress. However, the upstream regulator of exercise-induced vascular benefits is unclear. We aimed to investigate the involvement of peroxisome proliferator-activated receptor δ (PPARδ) in exercise-induced vascular functional improvement. We show that PPARδ is a crucial mediator for exercise to exert a beneficial effect on the vascular endothelium in diabetic mice. In db/db mice and high-fat diet-induced obese mice, 4 weeks of treadmill exercise restored endothelium-dependent vasodilation of aortas and flow-mediated vasodilation in mesenteric resistance arteries, whereas genetic ablation of Ppard abolished such improvements. Exercise induces AMPK activation and subsequent PPARδ activation, which help to reduce endoplasmic reticulum (ER) and oxidative stress, thus increasing NO bioavailability in endothelial cells and vascular tissues. Chemical chaperones 4-phenylbutyric acid and tauroursodeoxycholic acid decrease ER stress and protect against endothelial dysfunction in diabetic mice. The results demonstrate that PPARδ-mediated inhibition of ER stress contributes to the vascular benefits of exercise and provides potentially effective targets for treating diabetic vasculopathy.
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute, Li Ka Shing Institute of Health Sciences, School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong.|Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau.
authors.forename: Wai San
authors.initials: WS
authors.lastname: Cheang
authors.affiliation: School of Life Sciences, Chinese University of Hong Kong, Hong Kong.
authors.forename: Wing Tak
authors.initials: WT
authors.lastname: Wong
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute, Li Ka Shing Institute of Health Sciences, School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute, Li Ka Shing Institute of Health Sciences, School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute, Li Ka Shing Institute of Health Sciences, School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute, Li Ka Shing Institute of Health Sciences, School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong.
authors.forename: Chi Wai
authors.initials: CW
authors.lastname: Lau
authors.affiliation: School of Life Sciences, Chinese University of Hong Kong, Hong Kong.
authors.forename: Zhen Yu
authors.initials: ZY
authors.lastname: Chen
authors.affiliation: Department of Medicine and Therapeutics, Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong.
authors.forename: Ronald Ching Wan
authors.initials: RC
authors.lastname: Ma
authors.affiliation: Departments of Medicine and Pharmacology and Pharmacy, State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong.
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.affiliation: Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China.
authors.forename: Nanping
authors.initials: N
authors.lastname: Wang
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute, Li Ka Shing Institute of Health Sciences, School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong yu-huang@cuhk.edu.hk xytian@cuhk.edu.hk.
authors.forename: Xiao Yu
authors.initials: XY
authors.lastname: Tian
authors.affiliation: Institute of Vascular Medicine, Shenzhen Research Institute, Li Ka Shing Institute of Health Sciences, School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong yu-huang@cuhk.edu.hk xytian@cuhk.edu.hk.
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D003920:Diabetes Mellitus / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000503:physiopathology*; D059305:Diet, High-Fat; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D009213:Myography; D009569:Nitric Oxide; D009765:Obesity / Q000503:physiopathology; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000187:drug effects; D010654:Phenylbutyrates / Q000494:pharmacology; D010805:Physical Conditioning, Animal; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000235:genetics*
chemical_list: D010654:Phenylbutyrates; C091778:Ppard protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; C075773:4-phenylbutyric acid