Accelerated FASTK mRNA degradation induced by oxidative stress is responsible for the destroyed myocardial mitochondrial gene expression and respiratory function in alcoholic cardiomyopathy.
Accelerated FASTK mRNA degradation induced by oxidative stress is responsible for the destroyed myocardial mitochondrial gene expression and respiratory function in alcoholic cardiomyopathy.
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氧化应激诱导的 FASTK mRNA 加速降解是酒精性心肌病心肌线粒体基因表达和呼吸功能破坏的原因
DOI：
10.1016/j.redox.2020.101778
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发表时间：
2021-01
期刊：
影响因子：
11.4
通讯作者：
Pei J
中科院分区：
文献类型：
--
作者：
Zhang F;Wang K;Zhang S;Li J;Fan R;Chen X;Pei J
慢性酒精中毒破坏线粒体功能，经常导致酒精性心肌病（ACM）。fas激活的丝氨酸/苏氨酸激酶（FASTK）最近被认为是线粒体基因表达的关键转录后调节因子。然而，FASTK在心血管病理生理中的调节作用仍然完全未知。在实验性ACM模型中，心脏FASTK表达明显下降。乙醇通过NADPH氧化酶衍生的活性氧（ROS）在转录后水平直接抑制FASTK的表达。乙醇破坏了FASTK mRNA 3′-非翻译区（3′-UTR）的稳定性，加速了其衰变，这一过程被ROS的清除所阻断。regase -1 （Reg1）是一种调节mRNA稳定性的核糖核酸酶，在乙醇刺激的心肌细胞中被ROS诱导。Reg1直接结合FASTK mRNA 3 ' -UTR并促进其降解，而Reg1的沉默逆转了乙醇诱导的FASTK下调。与野生型对照相比，酒精相关的心肌形态学（肥大、纤维化和心肌细胞凋亡）和功能（射血分数降低和心肌细胞收缩受损）异常在FASTK缺陷小鼠中恶化。在机制上，FASTK消融抑制了NADH脱氢酶亚基6 （MTND6，一种编码复合体I亚基的线粒体基因）mRNA的产生，并减少了复合体I支持的呼吸。重要的是，通过心脏内注射AAV9-cTNT，心肌细胞特异性上调FASTK可减轻心肌线粒体功能障碍并抑制ACM进展。体外研究表明，FASTK过表达可改善乙醇诱导的MTND6 mRNA下调、复合物I失活和心肌细胞死亡，而这些有益作用被复合物I抑制剂鱼藤酮抵消。总的来说，ros通过Reg1加速FASTK mRNA降解是慢性乙醇摄入相关线粒体功能障碍和心肌病的基础。通过遗传方法恢复FASTK表达可能是一种很有前途的治疗ACM的策略。乙醇通过NOX/ROS/Regnase-1途径加速心脏FASTK mRNA降解。基因FASTK缺失通过抑制线粒体功能加重酒精性心肌病（ACM）。心脏过表达FASTK可预防ACM。
Chronic alcoholism disrupts mitochondrial function and often results in alcoholic cardiomyopathy (ACM). Fas-activated serine/threonine kinase (FASTK) is newly recognized as a key post-transcriptional regulator of mitochondrial gene expression. However, the modulatory role of FASTK in cardiovascular pathophysiology remains totally unknown. In experimental ACM models, cardiac FASTK expression markedly declined. Ethanol directly suppressed FASTK expression at post-transcriptional level through NADPH oxidase-derived reactive oxygen species (ROS). Ethanol destabilized FASTK mRNA 3′-untranslated region (3′-UTR) and accelerated its decay, which was blocked by the clearance of ROS. Regnase-1 (Reg1), a ribonuclease regulating mRNA stability, was induced by ROS in ethanol-stimulated cardiomyocytes. Reg1 directly bound to FASTK mRNA 3′-UTR and promoted its degradation, whereas silencing of Reg1 reversed ethanol-induced FASTK downregulation. Compared to wild type control, alcohol-related myocardial morphological (hypertrophy, fibrosis and cardiomyocyte apoptosis) and functional (reduced ejection fraction and compromised cardiomyocyte contraction) anomalies were worsened in FASTK deficient mice. Mechanistically, FASTK ablation repressed NADH dehydrogenase subunit 6 (MTND6, a mitochondrial gene encoding a subunit of complex I) mRNA production and reduced complex I-supported respiration. Importantly, cardiomyocyte-specific upregulation of FASTK through intra-cardiac AAV9-cTNT injection mitigated myocardial mitochondrial dysfunction and restrained ACM progression. In vitro study showed that overexpression of FASTK ameliorated ethanol-induced MTND6 mRNA downregulation, complex I inactivation, and cardiomyocyte death, whereas these beneficial effects were counteracted by rotenone, a complex I inhibitor. Collectively, ROS-accelerated FASTK mRNA degradation via Reg1 underlies chronic ethanol ingestion-associated mitochondrial dysfunction and cardiomyopathy. Restoration of FASTK expression through genetic approaches might be a promising therapeutic strategy for ACM. Ethanol accelerates cardiac FASTK mRNA degradation via NOX/ROS/Regnase-1 pathway. Genetic FASTK deletion exacerbates alcoholic cardiomyopathy (ACM) via repressing mitochondiral function. Cardiac overexpression of FASTK protects against ACM.
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影响因子：
37.8
作者：
Omiya, Shigemiki;Omori, Yosuke;Otsu, Kinya
通讯作者：
Otsu, Kinya
DOI：
10.1152/ajpheart.00214.2016
发表时间：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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影响因子：
4.6
作者：
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