TRPV1-mediated UCP2 upregulation ameliorates hyperglycemia-induced endothelial dysfunction

Cardiovasc Diabetol. 2013 Apr 22;12:69. doi: 10.1186/1475-2840-12-69.


Background: Diabetic cardiovascular complications are characterised by oxidative stress-induced endothelial dysfunction. Uncoupling protein 2 (UCP2) is a regulator of mitochondrial reactive oxygen species (ROS) generation and can antagonise oxidative stress, but approaches that enhance the activity of UCP2 to inhibit ROS are scarce. Our previous studies show that activation of transient receptor potential vanilloid 1 (TRPV1) by capsaicin can prevent cardiometabolic disorders. In this study, we conducted experiments in vitro and in vivo to investigate the effect of capsaicin treatment on endothelial UCP2 and oxidative stress. We hypothesised that TRPV1 activation by capsaicin attenuates hyperglycemia-induced endothelial dysfunction through a UCP2-mediated antioxidant effect.

Methods: TRPV1(-/-), UCP2(-/-) and db/db mice, as well as matched wild type (WT) control mice, were included in this study. Some mice were subjected to dietary capsaicin for 14 weeks. Arteries isolated from mice and endothelial cells were cultured. Endothelial function was examined, and immunohistological and molecular analyses were performed.

Results: Under high-glucose conditions, TRPV1 expression and protein kinase A (PKA) phosphorylation were found to be decreased in the cultured endothelial cells, and the effects of high-glucose on these molecules were reversed by the administration of capsaicin. Furthermore, high-glucose exposure increased ROS production and reduced nitric oxide (NO) levels both in endothelial cells and in arteries that were evaluated respectively by dihydroethidium (DHE) and DAF-2 DA fluorescence. Capsaicin administration decreased the production of ROS, restored high-glucose-induced endothelial dysfunction through the activation of TRPV1 and acted in a UCP2-dependent manner in vivo. Administration of dietary capsaicin for 14 weeks increased the levels of PKA phosphorylation and UCP2 expression, ameliorated the vascular oxidative stress and increased NO levels observed in diabetic mice. Prolonged dietary administration of capsaicin promoted endothelium-dependent relaxation in diabetic mice. However, the beneficial effect of capsaicin on vasorelaxation was absent in the aortas of UCP2(-/-) mice exposed to high-glucose levels.

Conclusion: TRPV1 activation by capsaicin might protect against hyperglycemia-induced endothelial dysfunction through a mechanism involving the PKA/UCP2 pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arteries / drug effects*
  • Capsaicin / pharmacology*
  • Cells, Cultured
  • Cyclic AMP-Dependent Protein Kinases / drug effects
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Diabetic Angiopathies
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Glucose / pharmacology*
  • In Vitro Techniques
  • Ion Channels / drug effects
  • Ion Channels / genetics
  • Ion Channels / metabolism*
  • Mice
  • Mice, Knockout
  • Mitochondrial Proteins / drug effects
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Nitric Oxide / metabolism
  • Oxidative Stress / drug effects
  • Phosphorylation / drug effects
  • Reactive Oxygen Species / metabolism
  • TRPV Cation Channels / drug effects
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism*
  • Uncoupling Protein 2
  • Up-Regulation
  • Vasodilation / drug effects


  • Ion Channels
  • Mitochondrial Proteins
  • Reactive Oxygen Species
  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • Ucp2 protein, mouse
  • Uncoupling Protein 2
  • Nitric Oxide
  • Cyclic AMP-Dependent Protein Kinases
  • Glucose
  • Capsaicin