硫化氢通过在人主动脉瓣间质细胞中诱导NRF2相关的促自噬作用来抑制与主动脉瓣变性相关的基因表达。

IF 3.5 2区 生物学 Q3 CELL BIOLOGY
Molecular and Cellular Biochemistry Pub Date : 2024-10-01 Epub Date: 2023-10-20 DOI:10.1007/s11010-023-04881-2
Naaleum Song, Jeong Eun Yu, Eunhye Ji, Kyoung-Hee Choi, Sahmin Lee
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引用次数: 0

摘要

主动脉瓣狭窄(AS)是最常见的瓣膜性心脏病,但由于缺乏精确的病理生理学知识,目前还没有有效的药物治疗方法可以延缓疾病的进展。AS患者主动脉瓣中硫化物:醌氧化还原酶(SQOR)和核因子红系2相关因子2(NRF2)的表达降低。然而,尚未发现SQOR和NRF2在AS病理生理学中的作用。我们研究了硫化氢(H2S)释放化合物对病变主动脉瓣间质细胞(AVICs)的影响,以解释SQOR的细胞机制,并阐明H2S治疗AS的医学价值。硫酸氢钠(NaHS)处理增加了SQOR和NRF2基因的表达,从而诱导了NRF2靶基因,如NAD(P)H醌脱氢酶1和胱硫醚γ-裂解酶。此外,NaHS剂量依赖性地降低了人AVICs中纤维化和炎症相关基因(MMP9、TNF-α、IL6)以及钙化相关基因(ALP、骨钙素、RUNX2、COL1A1)的表达水平。此外,NaHS激活AMPK-mTOR通路并抑制PI3K-AKT通路,从而在人类AVICs中产生促自噬作用。NRF2抑制剂Brustol减弱了NaHS诱导的AMPK激活,并降低了自噬标记物Beclin-1和LC3AB,表明H2S的作用机制与NRF2有关。总之,H2S降低了与主动脉瓣退化相关的基因表达水平,并激活了人类AVICs中与NRF2相关的AMPK-mTOR介导的自噬前功能。因此,H2S可能是开发AS治疗的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Hydrogen sulfide inhibits gene expression associated with aortic valve degeneration by inducing NRF2-related pro-autophagy effect in human aortic valve interstitial cells.

Hydrogen sulfide inhibits gene expression associated with aortic valve degeneration by inducing NRF2-related pro-autophagy effect in human aortic valve interstitial cells.

Aortic valve stenosis (AS) is the most common valvular heart disease but there are currently no effective medical treatments that can delay disease progression due to a lack of knowledge of the precise pathophysiology. The expression of sulfide: quinone oxidoreductase (SQOR) and nuclear factor erythroid 2-related factor 2 (NRF2) was decreased in the aortic valve of AS patients. However, the role of SQOR and NRF2 in the pathophysiology of AS has not been found. We investigated the effects of hydrogen sulfide (H2S)-releasing compounds on diseased aortic valve interstitial cells (AVICs) to explain the cellular mechanism of SQOR and elucidate the medical value of H2S for AS treatment. Sodium hydrosulfide (NaHS) treatment increased the expression of SQOR and NRF2 gene and consequently induced the NRF2 target genes, such as NAD(P)H quinone dehydrogenase 1 and cystathionine γ-lyase. In addition, NaHS dose-dependently decreased the expression level of fibrosis and inflammation-related genes (MMP9, TNF-α, IL6) and calcification-related genes (ALP, osteocalcin, RUNX2, COL1A1) in human AVICs. Furthermore, NaHS activated the AMPK-mTOR pathway and inhibited the PI3K-AKT pathway, resulting in a pro-autophagy effect in human AVICs. An NRF2 inhibitor, brusatol, attenuated NaHS-induced AMPK activation and decreased the autophagy markers Beclin-1 and LC3AB, suggesting that the mechanism of action of H2S is related to NRF2. In conclusion, H2S decreased gene expression levels related to aortic valve degeneration and activated AMPK-mTOR-mediated pro-autophagy function associated with NRF2 in human AVICs. Therefore, H2S could be a potential therapeutic target for the development of AS treatment.

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来源期刊
Molecular and Cellular Biochemistry
Molecular and Cellular Biochemistry 生物-细胞生物学
CiteScore
8.30
自引率
2.30%
发文量
293
审稿时长
1.7 months
期刊介绍: Molecular and Cellular Biochemistry: An International Journal for Chemical Biology in Health and Disease publishes original research papers and short communications in all areas of the biochemical sciences, emphasizing novel findings relevant to the biochemical basis of cellular function and disease processes, as well as the mechanics of action of hormones and chemical agents. Coverage includes membrane transport, receptor mechanism, immune response, secretory processes, and cytoskeletal function, as well as biochemical structure-function relationships in the cell. In addition to the reports of original research, the journal publishes state of the art reviews. Specific subjects covered by Molecular and Cellular Biochemistry include cellular metabolism, cellular pathophysiology, enzymology, ion transport, lipid biochemistry, membrane biochemistry, molecular biology, nuclear structure and function, and protein chemistry.
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