Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, China; Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Sciences at the Wenzhou Medical University, Wenzhou 325035, China; Pediatrics Research Institute, the Department of Pediatrics of the University of Louisville, Louisville 40202, USA.
Pediatrics Research Institute, the Department of Pediatrics of the University of Louisville, Louisville 40202, USA; First Hospital of Jilin University, Changchun 130021, China.
Redox Biol. 2018 May;15:405-417. doi: 10.1016/j.redox.2017.12.016. Epub 2018 Jan 2.
Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) by sulforaphane (SFN) protects from, and deletion of the Nrf2 gene exaggerates, diabetic cardiomyopathy. Angiotensin II (Ang II) plays a critical role in the development of diabetic cardiomyopathy. Therefore, whether SFN prevents Ang II-induced cardiomyopathy through activation of Nrf2 was examined using wild-type, global deletion of Nrf2 gene (Nrf2-KO) and cardiomyocyte-specific overexpression of Nrf2 gene (Nrf2-TG) mice.
Administration of a subpressor dose of Ang II to wild-type mice induced cardiac oxidative stress, inflammation, remodeling and dysfunction, all of which could be prevented by SFN treatment with Nrf2 up-regulation and activation. Nrf2-KO mice are susceptible, and Nrf2-TG mice are resistant, respectively, to Ang II-induced cardiomyopathy. Meanwhile, the ability of SFN to protect against Ang II-induced cardiac damage was lost in Nrf2-KO mice. Up-regulation and activation of Nrf2 by SFN is accompanied by activation of Akt, inhibition of glycogen synthase kinase (GSK)-3β, and accumulation of Fyn in nuclei. In vitro up-regulation of Nrf2 by SFN was abolished and nuclear Fyn accumulation was increased when cardiac cells were exposed to a PI3K inhibitor or GSK-3β-specific activator.
These results suggest that Nrf2 plays a central role in the prevention of Ang II-induced cardiomyopathy, and SFN prevents Ang II-induced cardiomyopathy partially via the Akt/GSK-3β/Fyn-mediated Nrf2 activation.
通过萝卜硫素 (SFN) 激活核因子红细胞 2 相关因子 2 (Nrf2) 可预防糖尿病心肌病，而 Nrf2 基因缺失则会加剧糖尿病心肌病。血管紧张素 II (Ang II) 在糖尿病心肌病的发展中起关键作用。因此，本研究使用野生型、Nrf2 基因全局缺失 (Nrf2-KO) 和心肌细胞特异性过表达 Nrf2 基因 (Nrf2-TG) 小鼠，研究 SFN 是否通过激活 Nrf2 来预防 Ang II 诱导的心肌病。
给予野生型小鼠亚加压剂量的 Ang II 可诱导心脏氧化应激、炎症、重构和功能障碍，而 SFN 治疗可通过上调和激活 Nrf2 来预防这些变化。Nrf2-KO 小鼠易患 Ang II 诱导的心肌病，而 Nrf2-TG 小鼠则具有抗性。同时，SFN 预防 Ang II 诱导的心脏损伤的能力在 Nrf2-KO 小鼠中丧失。SFN 通过上调和激活 Nrf2，伴随着 Akt 的激活、糖原合成酶激酶 (GSK)-3β 的抑制以及 Fyn 在核内的积累。当心脏细胞暴露于 PI3K 抑制剂或 GSK-3β 特异性激活剂时，SFN 体外上调 Nrf2 的作用被消除，核内 Fyn 积累增加。
这些结果表明，Nrf2 在预防 Ang II 诱导的心肌病中起核心作用，SFN 通过 Akt/GSK-3β/Fyn 介导的 Nrf2 激活部分预防 Ang II 诱导的心肌病。
