Liu Limei, Liu Jian, Tian Xiao Yu, Wong Wing Tak, Lau Chi Wai, Xu Aimin, Xu Gang, Ng Chi Fai, Yao Xiaoqiang, Gao Yuansheng, Huang Yu
1 Department of Physiology and Pathophysiology, Peking University Health Science Center , Peking, China .
Antioxid Redox Signal. 2014 Oct 10;21(11):1571-81. doi: 10.1089/ars.2013.5519. Epub 2014 Mar 12.
Although uncoupling protein 2 (UCP2) negatively regulates intracellular reactive oxygen species (ROS) production and protects vascular function, its participation in vascular benefits of drugs used to treat cardiometabolic diseases is largely unknown. This study investigated whether UCP2 and associated oxidative stress reduction contribute to the improvement of endothelial function by a dipeptidyl peptidase-4 inhibitor, sitagliptin, in hypertension.
Pharmacological inhibition of cyclooxygenase-2 (COX-2) but not COX-1 prevented endothelial dysfunction, and ROS scavengers reduced COX-2 mRNA and protein expression in spontaneously hypertensive rats (SHR) renal arteries. Angiotensin II (Ang II) evoked endothelium-dependent contractions (EDCs) in C57BL/6 and UCP2 knockout (UCP2KO) mouse aortae. Chronic sitagliptin administration attenuated EDCs in SHR arteries and Ang II-infused C57BL/6 mouse aortae and eliminated ROS overproduction in SHR arteries, which were reversed by glucagon-like peptide 1 receptor (GLP-1R) antagonist exendin 9-39, AMP-activated protein kinase (AMPK)α inhibitor compound C, and UCP2 inhibitor genipin. By contrast, sitagliptin unaffected EDCs in Ang II-infused UCP2KO mice. Sitagliptin increased AMPKα phosphorylation, upregulated UCP2, and downregulated COX-2 expression in arteries from SHR and Ang II-infused C57BL/6 mice. Importantly, exendin 9-39, compound C, and genipin reversed the inhibitory effect of GLP-1R agonist exendin-4 on Ang II-stimulated mitochondrial ROS rises in SHR endothelial cells. Moreover, exendin-4 improved the endothelial function of renal arteries from SHR and hypertensive patients.
We elucidate for the first time that UCP2 serves as an important signal molecule in endothelial protection conferred by GLP-1-related agents. UCP2 could be a useful target in treating hypertension-related vascular events.
UCP2 inhibits oxidative stress and downregulates COX-2 expression through GLP-1/GLP-1R/AMPKα cascade.
尽管解偶联蛋白2（UCP2）可负向调节细胞内活性氧（ROS）的产生并保护血管功能，但其是否参与用于治疗心脏代谢疾病的药物的血管益处尚不清楚。本研究调查了UCP2及相关氧化应激的降低是否有助于二肽基肽酶-4抑制剂西他列汀改善高血压患者的内皮功能。
环氧化酶-2（COX-2）而非COX-1的药理学抑制可预防内皮功能障碍，且ROS清除剂可降低自发性高血压大鼠（SHR）肾动脉中COX-2的mRNA和蛋白表达。血管紧张素II（Ang II）可引起C57BL/6和UCP2基因敲除（UCP2KO）小鼠主动脉的内皮依赖性收缩（EDC）。长期给予西他列汀可减弱SHR动脉和输注Ang II的C57BL/6小鼠主动脉中的EDC，并消除SHR动脉中的ROS过量产生，而胰高血糖素样肽1受体（GLP-1R）拮抗剂艾塞那肽9-39、AMP活化蛋白激酶（AMPK）α抑制剂化合物C和UCP2抑制剂京尼平可逆转这种作用。相比之下，西他列汀对输注Ang II的UCP2KO小鼠的EDC没有影响。西他列汀可增加SHR和输注Ang II的C57BL/6小鼠动脉中AMPKα的磷酸化，上调UCP2，并下调COX-2的表达。重要的是，艾塞那肽9-39、化合物C和京尼平可逆转GLP-1R激动剂艾塞那肽-4对SHR内皮细胞中Ang II刺激的线粒体ROS升高的抑制作用。此外，艾塞那肽-4可改善SHR和高血压患者肾动脉的内皮功能。
我们首次阐明UCP2是GLP-1相关药物赋予内皮保护作用的重要信号分子。UCP2可能是治疗高血压相关血管事件的有用靶点。
UCP2通过GLP-1/GLP-1R/AMPKα级联反应抑制氧化应激并下调COX-2的表达。
