Abstract
BackgroundDiabetic 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.MethodsTRPV1-/-, 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.ResultsUnder 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.ConclusionTRPV1 activation by capsaicin might protect against hyperglycemia-induced endothelial dysfunction through a mechanism involving the PKA/UCP2 pathway.
Highlights
Diabetic cardiovascular complications are characterised by oxidative stress-induced endothelial dysfunction
Activation of transient receptor potential vanilloid 1 (TRPV1) upregulates Uncoupling protein 2 (UCP2) through protein kinase A (PKA) phosphorylation We first showed that exposure to a high level of glucose (30 mmol/L) decreased TRPV1 expression and PKA phosphorylation in cultured endothelial cells compared with control cells and that these effects can be reversed by the administration of capsaicin (1 μmol/L)
Administration of capsaicin further increased the level of UCP2 in the cultured endothelial cells incubated in high-glucose conditions, but again, this effect of capsaicin was inhibited by antagonists of TRPV1 and inhibitor of PKA and by the UCP2 inhibitor, genipin (10 μmol/L) (Figure 1C)
Summary
Diabetic cardiovascular complications are characterised by oxidative stress-induced endothelial dysfunction. We hypothesised that TRPV1 activation by capsaicin attenuates hyperglycemia-induced endothelial dysfunction through a UCP2-mediated antioxidant effect. Reactive oxygen species (ROS) generated by hyperglycemia contribute to the development and progression of diabetic vascular complications and are linked to endothelial dysfunction [1,2,3,4]. Transient receptor potential vanilloid 1 (TRPV1), a polymodal nonselective cation channel, is expressed in sensory neurons and present in nonneuronal tissues including blood vessels, is a highly selective stimulated by capsaicin [17]. We showed that prolonged dietary administration of capsaicin increased NO production remarkably and improved endothelial function through specific targeting of TRPV1-mediated PKA/eNOS phosphorylation [20]. It is well documented that oxidative stress contributes to the vascular complications in diabetes, the factors that play a role in protecting against the associated endothelial dysfunction remain to be discovered
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