Liu Yunxia, Li Meina, Sun Meihua, Zhang Yaoting, Li Xuan, Sun Wanqing, Quan Nanhu
Department of Cardiovascular Center, The First Hospital of Jilin University, Changchun, 130021, China.
Department of Infection Control, The First Hospital of Jilin University, Changchun, 130021, China.
Free Radic Biol Med. 2021 Mar;165:385-394. doi: 10.1016/j.freeradbiomed.2021.01.048. Epub 2021 Feb 10.
Sestrin2 (Sesn2) is a stress-inducible protein that plays a critical role in the response to ischemic stress. We recently recognized that Sesn2 may protect the heart against ischemic insults by reducing the generation of reactive oxygen species (ROS). After 45 min of ischemia followed by 24 h of reperfusion, myocardial infarcts were significantly larger in Sesn2 KO hearts than in wild-type hearts. Isolated cardiomyocytes from wild-type hearts treated with hypoxia and reoxygenation (H/R) stress showed significantly greater Sesn2 levels, compared with normoxic hearts (p < 0.05). Intriguingly, the administration of adeno-associated virus 9-Sesn2 into Sesn2 knockout (KO) hearts rescued Sesn2 protein levels and significantly improved the cardiac function of Sesn2 KO mice exposed to ischemia and reperfusion. The rescued levels of Sesn2 in Sesn2 KO hearts significantly ameliorated ROS generation and the activation of ROS-related stress signaling pathways during ischemia and reperfusion. Moreover, the rescued Sesn2 levels in Sesn2 KO cardiomyocytes improved the maximal velocity of cardiomyocyte shortening by H/R stress. Rescued Sesn2 levels also improved peak height, peak shortening amplitude, and maximal velocity of the re-lengthening of Sesn2 KO cardiomyocytes subjected to H/R. Finally, the rescued Sesn2 levels significantly augmented intracellular calcium levels and reduced the mean time constant of transient calcium decay in Sesn2 KO cardiomyocytes exposed to H/R. Overall, these findings indicated that Sesn2 can act as an endogenous antioxidant to maintain intracellular redox homeostasis under ischemic stress conditions.
硒蛋白2（Sesn2）是一种应激诱导蛋白，在对缺血应激的反应中起关键作用。我们最近认识到，Sesn2可能通过减少活性氧（ROS）的产生来保护心脏免受缺血损伤。在缺血45分钟后再灌注24小时，Sesn2基因敲除（KO）小鼠心脏的心肌梗死面积明显大于野生型小鼠心脏。与常氧心脏相比，经缺氧复氧（H/R）应激处理的野生型心脏分离的心肌细胞中Sesn2水平显著升高（p<0.05）。有趣的是，向Sesn2基因敲除小鼠心脏注射腺相关病毒9-Sesn2可恢复Sesn2蛋白水平，并显著改善遭受缺血再灌注的Sesn2基因敲除小鼠的心脏功能。Sesn2基因敲除小鼠心脏中恢复的Sesn2水平显著改善了缺血再灌注期间ROS的产生以及ROS相关应激信号通路的激活。此外，Sesn2基因敲除心肌细胞中恢复的Sesn2水平提高了H/R应激下心肌细胞缩短的最大速度。恢复的Sesn2水平还改善了遭受H/R的Sesn2基因敲除心肌细胞再延长的峰值高度、峰值缩短幅度和最大速度。最后，恢复的Sesn2水平显著提高了Sesn2基因敲除心肌细胞在H/R刺激下的细胞内钙水平，并缩短了瞬时钙衰减的平均时间常数。总体而言，这些发现表明，Sesn2可以作为一种内源性抗氧化剂，在缺血应激条件下维持细胞内氧化还原稳态。
