Department of Cardiovascular Center, The First Hospital of Jilin University, Changchun, 130021, China; Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
Redox Biol. 2020 Sep;36:101637. doi: 10.1016/j.redox.2020.101637. Epub 2020 Jul 9.
Sestrin2 (Sesn2) is a stress sensor for the mammalian target of rapamycin complex 1 (mTORC1) pathway. Aging impairs cardiac mTORC1 activation, thereby sensitizing the heart to hypertrophy. C57BL/6 J young wild-type (young WT; 4-6 months), aged WT (24-26 months), and young Sestrin2 knockout mice (Y-Sesn2 KO; 4-6 months) underwent transverse aortic constriction (TAC) for pressure overload. Cardiac expression of Sesn2 decreased with age. At 4 weeks after TAC, aged WT and Y-Sesn2 KO exhibited larger hearts and impaired cardiac function, compared with young WT mice. Augmented phosphorylation of mTOR and downstream effectors; damaged mitochondria and elevated redox markers, as well as and impaired glucose and fatty acid oxidation were observed in aged WT and Y-Sesn2 KO hearts. A pressure overload-induced interaction between Sesn2 and GTPase-activating protein activity toward Rags 2 (GATOR2), which positively regulates mTORC1, was impaired in aged WT hearts. Adeno-associated virus 9-Sesn2 treatment rescued Sesn2 expression, attenuated mTORC1 activation, and increased pressure overload tolerance in aged WT and Y-Sesn2 KO hearts. These results indicated that cardiac Sesn2 acts as a pressure overload sensor for mTORC1. Furthermore, Sesn2 deficiency may cause increased sensitivity to hypertrophy in elderly individuals.
Sesn2（Sesn2）是哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）途径的应激传感器。衰老会损害心脏 mTORC1 的激活，从而使心脏对肥大敏感。C57BL/6J 年轻野生型（年轻 WT；4-6 个月）、年老 WT（24-26 个月）和年轻 Sesn2 敲除小鼠（Y-Sesn2 KO；4-6 个月）接受了主动脉缩窄（TAC）以产生压力超负荷。Sesn2 在心脏中的表达随着年龄的增长而减少。在 TAC 后 4 周，与年轻 WT 小鼠相比，年老 WT 和 Y-Sesn2 KO 表现出更大的心脏和受损的心脏功能。观察到年老 WT 和 Y-Sesn2 KO 心脏中的 mTOR 和下游效应物的磷酸化增强；线粒体受损和氧化还原标志物升高，以及葡萄糖和脂肪酸氧化受损。在年老 WT 心脏中，Sesn2 与 GTPase 激活蛋白活性对 Rag 2（GATOR2）之间的压力超负荷诱导相互作用受损，后者正向调节 mTORC1。腺相关病毒 9-Sesn2 处理挽救了 Sesn2 的表达，减弱了 mTORC1 的激活，并增加了年老 WT 和 Y-Sesn2 KO 心脏的压力超负荷耐受性。这些结果表明，心脏 Sesn2 作为 mTORC1 的压力超负荷传感器发挥作用。此外，Sesn2 缺乏可能导致老年人对肥大的敏感性增加。
