Taguchi Kumiko, Hida Mari, Matsumoto Takayuki, Kobayashi Tsuneo
Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University.
Biol Pharm Bull. 2015;38(12):1864-72. doi: 10.1248/bpb.b15-00403.
Diabetic vascular complication is one of the manifestations of endothelial dysfunction. Resveratrol (RV) is considered to be beneficial in protecting endothelial function. However, the exact protective effect and mechanisms involved have not been fully clarified. In this study, we investigated the relationship between Akt/endothelial nitric oxide synthase (eNOS) activation and RV in diabetes-induced endothelial dysfunction. Aortas were dissected and placed in organ chambers, and nitric oxide (NO) production in response to acetylcholine (ACh) and RV was measured. ACh-induced endothelium-dependent relaxation was markedly increased in controls by RV pretreatment. Furthermore, RV caused NO-dependent relaxation via the Akt signaling pathway, which was weaker in the aortas of diabetic mice than age-matched controls. To further examine the underlying mechanisms, we measured the phosphorylation of Akt and eNOS by Western blotting. RV caused the phosphorylation of Akt and eNOS in aortas, which was decreased in diabetic mice. However, RV augmented the impaired clonidine-induced relaxation in diabetic mice. Interestingly, the phosphorylation of Akt and eNOS was increased under stimulation with RV and clonidine only in diabetic mice. Thus, either RV or clonidine causes Akt-dependent NO-mediated relaxation, which is weaker in diabetic mice than controls. However, additional exposure to RV and clonidine has an augmenting effect on the Akt/eNOS signaling pathway under diabetic conditions. RV-induced Akt/eNOS activity may be a common link involved in the clonidine-induced Akt/eNOS activity, so RV and clonidine may have a synergistic effect.
糖尿病血管并发症是内皮功能障碍的表现之一。白藜芦醇（RV）被认为对保护内皮功能有益。然而，其确切的保护作用及相关机制尚未完全阐明。在本研究中，我们调查了Akt/内皮型一氧化氮合酶（eNOS）激活与RV在糖尿病诱导的内皮功能障碍中的关系。解剖主动脉并置于器官浴槽中，测量对乙酰胆碱（ACh）和RV反应时一氧化氮（NO）的生成。在对照组中，RV预处理显著增强了ACh诱导的内皮依赖性舒张。此外，RV通过Akt信号通路引起NO依赖性舒张，在糖尿病小鼠主动脉中这种作用比年龄匹配的对照组弱。为进一步研究潜在机制，我们通过蛋白质印迹法测量Akt和eNOS的磷酸化。RV导致主动脉中Akt和eNOS磷酸化，在糖尿病小鼠中这种磷酸化降低。然而，RV增强了糖尿病小鼠中可乐定诱导的受损舒张。有趣的是，仅在糖尿病小鼠中，RV和可乐定刺激下Akt和eNOS的磷酸化增加。因此，单独的RV或可乐定均可引起Akt依赖性NO介导的舒张，在糖尿病小鼠中这种舒张比对照组弱。然而，在糖尿病条件下，额外给予RV和可乐定对Akt/eNOS信号通路有增强作用。RV诱导的Akt/eNOS活性可能是可乐定诱导的Akt/eNOS活性所涉及的共同环节，所以RV和可乐定可能具有协同作用。
