Alpha-ketoglutarate is required for chronic hypoxia-induced cardiac remodeling.

IF 5 2区 生物学 Q2 CELL BIOLOGY
Daishi Tang, Yong Gu, Shasha Chen, Tong Niu, Jin'ao Zhu, Panpan Liu, Mingge Ding, Yanjie Guo
{"title":"Alpha-ketoglutarate is required for chronic hypoxia-induced cardiac remodeling.","authors":"Daishi Tang, Yong Gu, Shasha Chen, Tong Niu, Jin'ao Zhu, Panpan Liu, Mingge Ding, Yanjie Guo","doi":"10.1152/ajpcell.00257.2024","DOIUrl":null,"url":null,"abstract":"<p><p>Chronic hypoxia (CH) is commonly associated with various cardiovascular diseases, with cardiac hypertrophy being the most frequently observed alteration. Metabolic remodeling is another consequence seen in the hypoxic heart. However, the mechanistic linkage between metabolic remodeling and cardiac hypertrophy in the hypoxic heart remains unclear. In this study, wild-type C57BL/6J mice were subjected to CH for 4 wk. Echocardiography and morphological analysis were used to assess the cardiac effects. We found that 4 wk of CH led to significant cardiac hypertrophy in the mice, whereas cardiac function remained unchanged compared with normoxic mice. In addition, CH induced an elevation in cardiac alpha-ketoglutarate (α-KG) content. Promoting α-KG degradation in the CH hearts prevented CH-induced cardiac hypertrophy but led to noticeable cardiac dysfunction. Mechanistically, α-KG promoted the transcription of hypertrophy-related genes by regulating histone methylation. Silencing lysine-specific demethylase 5 (KDM5), a histone demethylation enzyme, blunted α-KG-induced transcription of hypertrophy-related genes. These data suggest that α-KG is required for CH-induced cardiac remodeling, thus establishing a connection between metabolic changes and cardiac remodeling in hypoxic hearts.<b>NEW & NOTEWORTHY</b> We reported that alpha-ketoglutarate (α-KG) is indispensable for chronic hypoxia (CH)-induced cardiac remodeling, which builds the bridge between metabolic intermediates and cardiac remodeling.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C728-C736"},"PeriodicalIF":5.0000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of physiology. Cell physiology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1152/ajpcell.00257.2024","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/29 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Chronic hypoxia (CH) is commonly associated with various cardiovascular diseases, with cardiac hypertrophy being the most frequently observed alteration. Metabolic remodeling is another consequence seen in the hypoxic heart. However, the mechanistic linkage between metabolic remodeling and cardiac hypertrophy in the hypoxic heart remains unclear. In this study, wild-type C57BL/6J mice were subjected to CH for 4 wk. Echocardiography and morphological analysis were used to assess the cardiac effects. We found that 4 wk of CH led to significant cardiac hypertrophy in the mice, whereas cardiac function remained unchanged compared with normoxic mice. In addition, CH induced an elevation in cardiac alpha-ketoglutarate (α-KG) content. Promoting α-KG degradation in the CH hearts prevented CH-induced cardiac hypertrophy but led to noticeable cardiac dysfunction. Mechanistically, α-KG promoted the transcription of hypertrophy-related genes by regulating histone methylation. Silencing lysine-specific demethylase 5 (KDM5), a histone demethylation enzyme, blunted α-KG-induced transcription of hypertrophy-related genes. These data suggest that α-KG is required for CH-induced cardiac remodeling, thus establishing a connection between metabolic changes and cardiac remodeling in hypoxic hearts.NEW & NOTEWORTHY We reported that alpha-ketoglutarate (α-KG) is indispensable for chronic hypoxia (CH)-induced cardiac remodeling, which builds the bridge between metabolic intermediates and cardiac remodeling.

慢性缺氧诱导的心脏重塑需要α-酮戊二酸。
慢性缺氧(CH)通常与各种心血管疾病有关,而心脏肥大是最常观察到的改变。代谢重塑是缺氧性心脏的另一个后果。然而,缺氧心脏中代谢重塑与心脏肥大之间的机理联系仍不清楚。在这项研究中,野生型 C57BL/6J 小鼠接受了为期四周的缺氧治疗。超声心动图和形态学分析被用来评估对心脏的影响。我们发现,与常氧小鼠相比,四周的 CH 会导致小鼠心脏明显肥大,而心脏功能保持不变。此外,CH 还诱导了心脏α-酮戊二酸(α-KG)含量的升高。促进α-KG在CH心脏中的降解可防止CH诱导的心脏肥大,但会导致明显的心脏功能障碍。从机制上讲,α-KG通过调节组蛋白甲基化促进肥大相关基因的转录。抑制组蛋白去甲基化酶赖氨酸特异性去甲基化酶5(KDM5)可减弱α-KG诱导的肥大相关基因的转录。这些数据表明,α-KG 是 CH 诱导的心脏重塑所必需的,从而建立了缺氧心脏代谢变化与心脏重塑之间的联系。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
9.10
自引率
1.80%
发文量
252
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信