Epigallocatechin-3-gallate restores mitochondrial homeostasis impairment by inhibiting HDAC1-mediated NRF1 histone deacetylation in cardiac hypertrophy
Epigallocatechin-3-gallate restores mitochondrial homeostasis impairment by inhibiting HDAC1-mediated NRF1 histone deacetylation in cardiac hypertrophy
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DOI：
10.1007/s11010-023-04768-2
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发表时间：
2023-06-02
影响因子：
4.3
通讯作者：
Tian，Jie
中科院分区：
文献类型：
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作者：
Li，Gu;Pan，Bo;Tian，Jie
失代偿性心肌肥大伴随着线粒体稳态受损，组蛋白乙酰化是否参与了这一过程尚不清楚。研究HDAC 1介导的NRF 1组蛋白去乙酰化在大鼠主动脉缩窄（TAC）诱导的肥大和苯肾上腺素（PE）诱导的肥大心肌细胞中的作用。与未接受表没食子儿茶素没食子酸酯（EGCG）的TAC相比，给予HDAC 1抑制剂表没食子儿茶素没食子酸酯（EGCG）可恢复心脏功能，降低心脏/体重和纤维化，增加TAC中mtDNA/nDNA的比率和LysoTracker+ CM的百分比。在PE处理的肥大H9 C2细胞中，EGCG减弱细胞肥大，增加LC 3B II+MitoTracker+斑点，以及mtDNA/nDNA的比率。有趣的是，在TAC或PE诱导的肥大心脏或细胞中，NRF 1的表达分别降低，而不是PGC-1α的表达，而EGCG在体外上调NRF 1和PGC-1α。EGCG处理也增加了PGC-1α和NRF 1之间的相互作用。除了抑制HDAC 1的表达外，EGCG还降低了HDAC 1在PGC-1α和NRF 1启动子区的结合，并增加了acH 3 K9或acH 3 K14在PGC-1α和NRF 1启动子区的结合。在新生大鼠心肌细胞中，恢复的NRF 1，TFAM和FUNDC 1被HDAC 1的过表达所废除。总的来说，数据表明，通过抑制HDAC 1介导的组蛋白脱乙酰化，EGCG避免了NRF 1的减少。NRF 1组蛋白的乙酰化可能在维持心肌肥大相关的线粒体稳态中起关键作用。
Decompensated cardiac hypertrophy is accompanied by impaired mitochondrial homeostasis, whether histone acetylation is involved in this process is yet to be determined. The role of HDAC1-mediated NRF1 histone deacetylation was investigated in transverse aortic constriction (TAC)-induced hypertrophy in rats and phenylephrine (PE)-induced hypertrophic cardiomyocytes. Administration of epigallocatechin-3-gallate (EGCG), an inhibitor of HDAC1, restored cardiac function, decreased heart/body weight and fibrosis, increased the ratio of mtDNA/nDNA and the percentage of LysoTracker+CMs in TAC, compared with TAC without receiving EGCG. In PE-treated hypertrophic H9C2 cells, EGCG attenuated cell hypertrophy and increased LC3B II+MitoTracker+puncta, as well as the ratio of mtDNA/nDNA. Interestingly, NRF1 but not PGC-1α expression was decreased in TAC- or PE-induced hypertrophic hearts or cells, respectively, while EGCG upregulated both NRF1 and PGC-1α in vitro. EGCG treatment also increased the interaction between PGC-1α and NRF1. In addition to inhibiting HDAC1 expression, EGCG decreased the binding of HDAC1 and increased the binding of acH3K9 or acH3K14 in the promotor regions of PGC-1α and NRF1. In neonatal rat cardiomyocytes, restored NRF1, TFAM and FUNDC1 were abolished by the overexpression of HDAC1. Collectively, data suggest that NRF1 reduction was averted by EGCG via inhibiting HDAC1-mediated histone deacetylation. Acetylation of NRF1 histone may play a key role in maintaining mitochondrial homeostasis associated with cardiac hypertrophy.