Nrf2 deficiency prevents reductive stress-induced hypertrophic cardiomyopathy
Nrf2 deficiency prevents reductive stress-induced hypertrophic cardiomyopathy
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DOI：
10.1093/cvr/cvt150
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发表时间：
2013-10-01
影响因子：
10.8
通讯作者：
Rajasekaran, Namakkal S.
中科院分区：
文献类型：
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作者：
Kannan, Sankaranarayanan;Muthusamy, Vasanthi R.;Rajasekaran, Namakkal S.
在表达人CryAB （hmCryAB）突变体的转基因小鼠中，突变蛋白聚集（PA）心肌病（MPAC）的特征是减少应激（RS）、PA（伴侣和细胞骨架成分）和心室功能障碍。核红细胞2样因子-2 （Nrf2）的持续激活可引起RS，从而导致蛋白毒性心脏病。这项临床前研究的目的是：(i)研究破坏nrf2 -抗氧化信号是否能预防RS并恢复表达突变伴侣的心脏中的氧化还原稳态；（ii）阐明延缓蛋白毒性心脏病的机制。本研究采用非转基因（NTG）、MPAC转基因（TG）和MPAC-TG: nrf2缺陷（Nrf2-def）小鼠。在67月龄和10月龄时评估Nrf2减少（Nrf2）对RS介导的TG小鼠MPAC的影响。Nrf2的减少可以预防RS，并将TG小鼠的生存期（50周）延长2025周。TG:Nrf2-def小鼠甚至在60周时也没有表现出心脏肥厚，而MPAC-TG小鼠在2428周龄时开始出现病理性肥厚和心力衰竭。与TG小鼠相比，TG:Nrf2-def在7个月时心肌蛋白聚集明显减少。在TG:Nrf2-def小鼠中预防RS和维持氧化还原稳态可改善PA，导致蛋白泛素化降低。Nrf2缺乏可以恢复氧化还原稳态，从而减少突变蛋白的聚集，从而延缓RS和有毒蛋白聚集引起的蛋白毒性病理性心脏重构。
Mutant protein aggregation (PA) cardiomyopathy (MPAC) is characterized by reductive stress (RS), PA (of chaperones and cytoskeletal components), and ventricular dysfunction in transgenic mice expressing human mutant CryAB (hmCryAB). Sustained activation of nuclear erythroid-2 like factor-2 (Nrf2) causes RS, which contributes to proteotoxic cardiac disease. The goals of this pre-clinical study were to (i) investigate whether disrupting Nrf2-antioxidant signalling prevents RS and rescues redox homeostasis in hearts expressing the mutant chaperone and (ii) elucidate mechanisms that could delay proteotoxic cardiac disease.Non-transgenic (NTG), transgenic (TG) with MPAC and MPAC-TG:Nrf2-deficient (Nrf2-def) mice were used in this study. The effects of Nrf2 diminution (Nrf2) on RS mediated MPAC in TG mice were assessed at 67 and 10 months of age. The diminution of Nrf2 prevented RS and prolonged the survival of TG mice (50 weeks) by an additional 2025 weeks. The TG:Nrf2-def mice did not exhibit cardiac hypertrophy at even 60 weeks, while the MPAC-TG mice developed pathological hypertrophy and heart failure starting at 2428 weeks of age. Aggregation of cardiac proteins was significantly reduced in TG:Nrf2-def when compared with TG mice at 7 months. Preventing RS and maintaining redox homeostasis in the TG:Nrf2-def mice ameliorated PA, leading to decreased ubiquitination of proteins.Nrf2 deficiency rescues redox homeostasis, which reduces aggregation of mutant proteins, thereby delaying the proteotoxic pathological cardiac remodelling caused by RS and toxic protein aggregates.