Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China.
Cardiovasc Diabetol. 2013 Apr 22;12:69. doi: 10.1186/1475-2840-12-69.
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.
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.
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.
TRPV1 activation by capsaicin might protect against hyperglycemia-induced endothelial dysfunction through a mechanism involving the PKA/UCP2 pathway.
糖尿病心血管并发症的特征是氧化应激诱导的内皮功能障碍。解偶联蛋白 2（UCP2）是线粒体活性氧（ROS）产生的调节剂，可拮抗氧化应激，但增强 UCP2 活性以抑制 ROS 的方法却很少。我们之前的研究表明，辣椒素激活瞬时受体电位香草酸 1（TRPV1）可以预防心脏代谢紊乱。在这项研究中，我们进行了体外和体内实验，以研究辣椒素处理对内皮 UCP2 和氧化应激的影响。我们假设，辣椒素通过 TRPV1 激活通过 UCP2 介导的抗氧化作用减轻高血糖诱导的内皮功能障碍。
本研究纳入了 TRPV1（-/-）、UCP2（-/-）和 db/db 小鼠以及匹配的野生型（WT）对照小鼠。一些小鼠接受了 14 周的饮食辣椒素处理。从小鼠中分离出动脉并培养内皮细胞。检查内皮功能，并进行免疫组织化学和分子分析。
在高葡萄糖条件下，发现培养的内皮细胞中 TRPV1 表达和蛋白激酶 A（PKA）磷酸化减少，高葡萄糖对这些分子的作用被辣椒素的给药逆转。此外，高葡萄糖暴露增加了 ROS 的产生并降低了内皮细胞和动脉中一氧化氮（NO）的水平，分别通过二氢乙啶（DHE）和 DAF-2 DA 荧光进行评估。辣椒素给药减少了 ROS 的产生，通过激活 TRPV1 恢复了高葡萄糖诱导的内皮功能障碍，并在体内以 UCP2 依赖的方式起作用。14 周的饮食辣椒素给药增加了 PKA 磷酸化和 UCP2 表达水平，改善了糖尿病小鼠中观察到的血管氧化应激和增加的 NO 水平。长期饮食辣椒素给药促进了糖尿病小鼠的内皮依赖性松弛。然而，在暴露于高葡萄糖水平的 UCP2（-/-）小鼠的主动脉中，辣椒素对血管松弛的有益作用不存在。
辣椒素通过 TRPV1 激活可能通过涉及 PKA/UCP2 途径的机制来保护内皮免受高血糖诱导的功能障碍。
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