PPARδ Is Required for Exercise to Attenuate Endoplasmic Reticulum Stress and Endothelial Dysfunction in Diabetic Mice

Diabetes. 2017 Feb;66(2):519-528. doi: 10.2337/db15-1657. Epub 2016 Nov 17.

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.

MeSH terms

  • Animals
  • Aorta / drug effects
  • Aorta / physiopathology
  • Blood Pressure / drug effects
  • Blood Pressure / genetics
  • Diabetes Mellitus / physiopathology*
  • Diabetic Angiopathies / physiopathology*
  • Diet, High-Fat
  • Endoplasmic Reticulum Stress / drug effects
  • Endoplasmic Reticulum Stress / genetics*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / physiopathology*
  • Male
  • Mesenteric Arteries / drug effects
  • Mesenteric Arteries / physiopathology*
  • Mice
  • Mice, Knockout
  • Myography
  • Nitric Oxide
  • Obesity / physiopathology
  • Organ Culture Techniques
  • Oxidative Stress / drug effects
  • Phenylbutyrates / pharmacology
  • Physical Conditioning, Animal*
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Taurochenodeoxycholic Acid / pharmacology
  • Vasodilation / drug effects
  • Vasodilation / genetics*

Substances

  • Phenylbutyrates
  • Ppard protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • Nitric Oxide
  • Taurochenodeoxycholic Acid
  • ursodoxicoltaurine
  • 4-phenylbutyric acid