Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance [bulkRNA-Seq]

Heart disease can be caused by ischemic coronary artery injury, hypertension, and chemotherapy, all of which lead to loss or dysfunction of cardiac muscle. The adult mammalian heart lacks the ability to regenerate. In contrast, the heart of neonatal mice, within the first week after birth, possesses a unique ability to regenerate lost myocardium following injury, mediated by proliferation of cardiomyocytes. The mechanisms whereby neonatal cardiomyocytes adapt to injury-induced stress conditions and activate regenerative cellular programs remain to be defined. Here, we show that Nrf1, an endoplasmic reticulum (ER) bound transcription factor, is expressed in regenerating cardiomyocytes. Genetic deletion of Nrf1 prevented cardiomyocytes from activating a transcriptional program required for heart regeneration, revealed by single-nucleus RNA sequencing (snRNA-seq). Conversely, adeno-associated virial (AAV) overexpression of Nrf1 protected the adult mouse heart from ischemia/reperfusion (I/R) injury. Nrf1 also protected human induced pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) from doxorubicin-induced cardiotoxicity. The protective function of Nrf1 is mediated by a dual stress response mechanism involving activation of the proteasome and redox balance. Our findings reveal a mechanistic interplay between adaptive stress responses and heart regeneration, and highlight the central role of Nrf1 in these processes. Exmination of transcriptome changes in neonatal rat ventricular cardiomyocytes overexpresing Nrf1 or Nrf2 .

缺血性冠状动脉损伤、高血压及化疗均可引发心脏病，三者均会导致心肌丢失或功能异常。成年哺乳动物心脏不具备再生能力。与之相反，新生小鼠在出生后第一周内的心脏，可通过心肌细胞（cardiomyocytes）增殖介导损伤后丢失心肌的再生，具备独特的再生能力。新生心肌细胞如何适应损伤诱导的应激环境并激活再生细胞程序，其相关机制仍有待阐明。本研究发现，内质网（endoplasmic reticulum, ER）结合型转录因子Nrf1在再生心肌细胞中表达。单核RNA测序（single-nucleus RNA sequencing, snRNA-seq）结果显示，敲除Nrf1可阻止心肌细胞激活心脏再生所需的转录程序。相反，腺相关病毒（adeno-associated virus, AAV）介导的Nrf1过表达可保护成年小鼠心脏免受缺血再灌注（ischemia/reperfusion, I/R）损伤。Nrf1还可保护人类诱导多能干细胞衍生心肌细胞（human induced pluripotent stem cell-derived cardiomyocytes, hPSC-CMs）免受阿霉素诱导的心肌毒性。Nrf1的保护功能由涉及蛋白酶体激活与氧化还原稳态调控的双重应激反应机制介导。本研究结果揭示了适应性应激反应与心脏再生之间的机制性相互作用，并凸显了Nrf1在这些过程中的核心作用。本研究对过表达Nrf1或Nrf2的新生大鼠心室心肌细胞的转录组变化进行了检测分析。