Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan.
Department of Cardiology and Nephrology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan.
Arch Pharm Res. 2020 Mar;43(3):286-296. doi: 10.1007/s12272-019-01188-z. Epub 2019 Nov 11.
Nrf2 regulates redox homeostasis in cells by coordinately regulating a range of antioxidant enzymes and proteins. An increase in oxidative stress is one of the hallmarks of aging, and Nrf2 protein levels and activity decrease with aging. Decreased mitochondrial functions, such as decreased ATP production, also occur with aging, leading to the increased generation of reactive oxygen species (ROS) and oxidative stress. Thus, understanding the relationships between Nrf2 and the mitochondria is important for clarifying the regulatory mechanisms of aging. It is becoming clear that Nrf2 is activated in a tissue-specific manner in response to mitochondrial or NADPH oxidase-generated ROS. As the heart consists of postmitotic cells that utilize ATP produced mainly by mitochondrial oxidative phosphorylation, cardiomyocytes are equipped with highly sophisticated mitochondrial quality control mechanisms. Consistent with these findings, it has been reported that Nrf2 in the heart is regulated via a specific translational mechanism and that Nrf2 activation confers cardioprotective effects in various disease models. Thus, Nrf2 is a promising target for anti-aging strategies to combat age-related heart diseases, such as age-related cardiomyopathy.
Nrf2 通过协调调节一系列抗氧化酶和蛋白质来调节细胞内的氧化还原稳态。氧化应激的增加是衰老的标志之一，而 Nrf2 蛋白水平和活性随着衰老而降低。衰老伴随着线粒体功能的下降，例如 ATP 产生减少，这导致活性氧（ROS）和氧化应激的产生增加。因此，了解 Nrf2 和线粒体之间的关系对于阐明衰老的调节机制非常重要。越来越明显的是，Nrf2 会针对线粒体或 NADPH 氧化酶产生的 ROS 以组织特异性的方式被激活。由于心脏由利用主要通过线粒体氧化磷酸化产生的 ATP 的有丝分裂后细胞组成，心肌细胞配备了高度复杂的线粒体质量控制机制。与这些发现一致，据报道，心脏中的 Nrf2 通过特定的翻译机制进行调节，并且 Nrf2 的激活在各种疾病模型中赋予了心脏保护作用。因此，Nrf2 是对抗与年龄相关的心脏病（如年龄相关性心肌病）等与年龄相关的心脏疾病的抗衰老策略的有前途的靶标。
