Cardiac Aging and Redox Signaling Laboratory, Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Department of Physiology, NIH BD2K Center of Excellence for Biomedical Computing at UCLA, University of California, Los Angeles, California, USA.
Antioxid Redox Signal. 2020 Jun;32(18):1293-1312. doi: 10.1089/ars.2019.7808.
Redox homeostasis is tightly controlled and regulates key cellular signaling pathways. The cell's antioxidant response provides a natural defense against oxidative stress, but excessive antioxidant generation leads to reductive stress (RS). This study elucidated how chronic RS, caused by constitutive activation of nuclear erythroid related factor-2 (caNrf2)-dependent antioxidant system, drives pathological myocardial remodeling. Upregulation of antioxidant transcripts and proteins in caNrf2-TG hearts (TGL and TGH; transgenic-low and -high) dose dependently increased glutathione (GSH) redox potential and resulted in RS, which over time caused pathological cardiac remodeling identified as hypertrophic cardiomyopathy (HCM) with abnormally increased ejection fraction and diastolic dysfunction in TGH mice at 6 months of age. While the TGH mice exhibited 60% mortality at 18 months of age, the rate of survival in TGL was comparable with nontransgenic (NTG) littermates. Moreover, TGH mice had severe cardiac remodeling at ∼6 months of age, while TGL mice did not develop comparable phenotypes until 15 months, suggesting that even moderate RS may lead to irreversible damages of the heart over time. Pharmacologically blocking GSH biosynthesis using BSO (l-buthionine-SR-sulfoximine) at an early age (∼1.5 months) prevented RS and rescued the TGH mice from pathological cardiac remodeling. Here we demonstrate that chronic RS causes pathological cardiomyopathy with diastolic dysfunction in mice due to sustained activation of antioxidant signaling. Our findings demonstrate that chronic RS is intolerable and adequate to induce heart failure (HF). Antioxidant-based therapeutic approaches for human HF should consider a thorough evaluation of redox state before the treatment.
氧化还原平衡受到严格控制，并调节关键的细胞信号通路。细胞的抗氧化反应为对抗氧化应激提供了自然防御，但过度的抗氧化生成会导致还原性应激（RS）。本研究阐明了核红细胞相关因子-2（caNrf2）依赖性抗氧化系统的组成性激活引起的慢性 RS 如何驱动病理性心肌重构。在 caNrf2-TG 心脏（TGL 和 TGH；转基因低和高）中，抗氧化转录物和蛋白质的上调呈剂量依赖性增加谷胱甘肽（GSH）氧化还原电势，并导致 RS，随着时间的推移导致病理性心脏重构，表现为肥厚型心肌病（HCM），TGH 小鼠在 6 个月时射血分数异常增加和舒张功能障碍。虽然 TGH 小鼠在 18 个月时的死亡率为 60%，但 TGL 小鼠的存活率与非转基因（NTG）同窝仔相似。此外，TGH 小鼠在约 6 个月时出现严重的心脏重构，而 TGL 小鼠直到 15 个月才出现可比表型，表明即使是中度 RS 也可能随着时间的推移导致心脏不可逆损伤。早期（约 1.5 个月）使用 BSO（l-buthionine-SR-sulfoximine）抑制 GSH 生物合成来药理学阻断 GSH 生物合成，可防止 RS 并使 TGH 小鼠免于病理性心脏重构。本研究证明，慢性 RS 由于抗氧化信号的持续激活，导致小鼠发生伴有舒张功能障碍的病理性心肌病。我们的研究结果表明，慢性 RS 是无法耐受的，足以引起心力衰竭（HF）。用于人类 HF 的基于抗氧化剂的治疗方法在治疗前应充分评估氧化还原状态。
