Li Yuefang, Huang Yan, Cheng Xi, He Youjun, Hu Xin
Cadre Ward the No.901 Hospital of the Joint Logistics Support Unit of the Chinese People's Liberation Army, Hefei, Anhui 230031, P.R. China.
Korean J Physiol Pharmacol. 2021 Jul 1;25(4):281-296. doi: 10.4196/kjpp.2021.25.4.281.
The beneficial effects of hypoxic preconditioning are abolished in the diabetes. The present study was designed to investigate the protective effects and mechanisms of repeated episodes of whole body hypoxic preconditioning (WBHP) in db/db mice. The protective effects of preconditioning were explored on diabetesinduced vascular dysfunction, cognitive impairment and ischemia-reperfusion (IR)-induced increase in myocardial injury. Sixteen-week old db/db (diabetic) and C57BL/6 (non-diabetic) mice were employed. There was a significant impairment in cognitive function (Morris Water Maze test), endothelial function (acetylcholineinduced relaxation in aortic rings) and a significant increase in IR-induced heart injury (Langendorff apparatus) in db/db mice. WBHP stimulus was given by exposing mice to four alternate cycles of low (8%) and normal air O for 10 min each. A single episode of WBHP failed to produce protection; however, two and three episodes of WBHP significantly produced beneficial effects on the heart, brain and blood vessels. There was a significant increase in the levels of brain-derived neurotrophic factor (BDNF) and nitric oxide (NO) in response to 3 episodes of WBHP. Moreover, pretreatment with the BDNF receptor, TrkB antagonist (ANA-12) and NO synthase inhibitor (LNAME) attenuated the protective effects imparted by three episodes of WBHP. These pharmacological agents abolished WBHP-induced restoration of p-GSK-3β/GSK-3β ratio and Nrf2 levels in IR-subjected hearts. It is concluded that repeated episodes of WHBP attenuate cognitive impairment, vascular dysfunction and enhancement in IRinduced myocardial injury in diabetic mice be due to increase in NO and BDNF levels that may eventually activate GSK-3β and Nrf2 signaling pathway to confer protection.
低氧预处理的有益作用在糖尿病状态下会消失。本研究旨在探讨反复进行全身低氧预处理（WBHP）对db/db小鼠的保护作用及其机制。研究了预处理对糖尿病诱导的血管功能障碍、认知障碍以及缺血再灌注（IR）诱导的心肌损伤增加的保护作用。选用16周龄的db/db（糖尿病）小鼠和C57BL/6（非糖尿病）小鼠。db/db小鼠在认知功能（莫里斯水迷宫试验）、内皮功能（主动脉环中乙酰胆碱诱导的舒张）方面存在显著损害，并且在IR诱导的心脏损伤（Langendorff装置）方面显著增加。通过将小鼠暴露于低氧（8%）和正常空气氧的四个交替循环中，每次10分钟来给予WBHP刺激。单次WBHP刺激未能产生保护作用；然而，两次和三次WBHP刺激对心脏、大脑和血管产生了显著的有益作用。响应三次WBHP刺激，脑源性神经营养因子（BDNF）和一氧化氮（NO）水平显著升高。此外，用BDNF受体TrkB拮抗剂（ANA - 12）和NO合酶抑制剂（LNAME）预处理减弱了三次WBHP刺激所赋予的保护作用。这些药物消除了WBHP诱导的IR处理心脏中p - GSK - 3β/GSK - 3β比值和Nrf2水平的恢复。结论是，反复进行的WHBP减轻了糖尿病小鼠的认知障碍和血管功能障碍，并增强了对IR诱导的心肌损伤的保护作用，这可能是由于NO和BDNF水平升高，最终激活GSK - 3β和Nrf2信号通路从而发挥保护作用。
