Exogenous H(2)S initiating Nrf2/GPx4/GSH pathway through promoting Syvn1-Keap1 interaction in diabetic hearts.
Exogenous H(2)S initiating Nrf2/GPx4/GSH pathway through promoting Syvn1-Keap1 interaction in diabetic hearts.
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DOI：
10.1038/s41420-023-01690-w
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发表时间：
2023-10-24
影响因子：
7
通讯作者：
Zhang, Weihua
中科院分区：
文献类型：
--
作者：
Wang, Mengyi;Tang, Jingyuan;Zhang, Shiwu;Pang, Kemiao;Zhao, Yajun;Liu, Ning;Huang, Jiayi;Kang, Jiaxin;Dong, Shiyun;Li, Hongxia;Tian, Zhen;Duan, Binhong;Lu, Fanghao;Zhang, Weihua
过量的ROS积累有助于2型糖尿病的心脏损伤。硫化氢（H2S）是一种重要的内源性气体递质，可减轻糖尿病心肌病（DCM）的心脏损伤。然而，潜在的机制仍不清楚。在这项研究中，我们研究了NaHS对db/db小鼠腹腔注射20周和HL-1心肌细胞高糖（HG）、棕榈酸盐（PA）和NaHS对HL-1心肌细胞48 h的影响。HG和PA处理的db/db小鼠和HL-1心肌细胞的H2S水平降低，NaHS使其恢复。外源性H2S激活db/db小鼠核因子-红细胞2相关因子2 (Nrf2)/谷胱甘肽过氧化物酶4 (GPx4)/谷胱甘肽（GSH）通路，抑制铁凋亡，减轻线粒体凋亡。然而，这些影响在Nrf2敲除后被消除。NaHS处理通过保留Keap1的E3连接酶Syvn1，提高kelch样ECH-associated protein （Keap1）的泛素化水平，导致Nrf2核易位。H2S促进了Syvn1-cys115位点的磺化，这是一种翻译后修饰。在暴露于HG和PA的心肌细胞中转染Syvn1 C115A可部分减弱NaHS对Nrf2和细胞死亡的影响。我们的研究结果表明，外源H2S通过促进Syvn1-Keap1相互作用来调节Nrf2/GPx4/GSH通路，从而减少DCM中的铁死亡和线粒体凋亡。
Excessive ROS accumulation contributes to cardiac injury in type 2 diabetes mellitus. Hydrogen sulfide (H2S) is a vital endogenous gasotransmitter to alleviate cardiac damage in diabetic cardiomyopathy (DCM). However, the underlying mechanisms remain unclear. In this study, we investigated the effects of NaHS administration in db/db mice via intraperitoneal injection for 20 weeks and the treatment of high glucose (HG), palmitate (PA) and NaHS in HL-1 cardiomyocytes for 48 h, respectively. H2S levels were decreased in hearts of db/db mice and HL-1 cardiomyocytes exposed to HG and PA, which were restored by NaHS. Exogenous H2S activated the nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPx4)/glutathione (GSH) pathway, suppressed ferroptosis and mitigated mitochondrial apoptosis in db/db mice. However, these effects were abrogated after Nrf2 knockdown. NaHS treatment elevated the ubiquitination level of Kelch-like ECH-associated protein (Keap1) by preserving its E3 ligase synoviolin (Syvn1), resulting in Nrf2 nuclear translocation. H2S facilitated the sulfhydration of Syvn1-cys115 site, a post-translational modification. Transfecting Syvn1 C115A in cardiomyocytes exposed to HG and PA partially attenuated the effects of NaHS on Nrf2 and cell death. Our findings suggest that exogenous H2S regulates Nrf2/GPx4/GSH pathway by promoting the Syvn1-Keap1 interaction to reduce ferroptosis and mitochondrial apoptosis in DCM.
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影响因子：
13.8
作者：
Chen QM
通讯作者：
Chen QM
影响因子：
7.4
作者：
Kopacz A;Kloska D;Forman HJ;Jozkowicz A;Grochot-Przeczek A
通讯作者：
Grochot-Przeczek A
影响因子：
5.6
作者：
Volkamer, Andrea;Griewel, Axel;Rarey, Matthias
通讯作者：
Rarey, Matthias
影响因子：
44.1
作者：
Tang D;Chen X;Kang R;Kroemer G
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Kroemer G
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影响因子：
11.4
作者：
Xu, Yang;Li, Yuting;Li, Jiaxin;Chen, Wei
通讯作者：
Chen, Wei