在斑马鱼中,lim1的缺失通过激活gp130/Jak1/Stat3通路导致心脏重构异常和心力衰竭。

IF 6.6 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Wuming Qin, Xiaobo Yang, Lu Zhang, Linghui Cao, Shi Ouyang, Dafeng Yang, Yangzhao Zhou, Anji Chen, Tao Liao, Xinyu Zhu, Yuting Liu, Wei Tang, Tongtong Ma, Yiyue Tang, Yonghe Ding, Yun Deng
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引用次数: 0

摘要

LIM锌指结构域1 (LIMS1)是一种进化保守的LIM结构域衔接蛋白,涉及多种病理,包括癌症和神经系统疾病。然而,其在心脏疾病中的作用及其潜在机制尚不清楚。在此,我们探讨LIMS1在心脏重塑和心力衰竭中的功能和机制。我们在扩张型心肌病(DCM)患者和小鼠心肌细胞中发现了LIMS1表达升高,表明LIMS1失调有助于心脏病理。利用CRISPR/Cas9技术,我们建立了lims1功能缺失突变体的斑马鱼模型,该模型表现出严重的心室重构、收缩功能障碍和过早死亡,证明了lims1在维持心脏完整性方面的重要作用。转录组学分析揭示了gp130/Jak1/Stat3信号在lims1缺陷心脏中的激活。引人注目的是,Stat3或c-Fos的药理学抑制部分地挽救了心肌病表型。我们的研究结果揭示了lim1缺陷通过gp130/Jak1/Stat3过度激活导致心力衰竭的潜在机制,为心脏重塑和潜在的治疗策略提供了见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Loss of lims1 causes aberrant cardiac remodeling and heart failure via activating gp130/Jak1/Stat3 pathway in zebrafish.

LIM zinc finger domain containing 1 (LIMS1), an evolutionally conserved LIM domain adaptor protein, is implicated in diverse pathologies, including cancer and neurological disorders. However, its roles in cardiac diseases and the underlying mechanisms remain unclear. Here, we explore the functions and mechanisms of LIMS1 in cardiac remodeling and heart failure. We identify the elevated LIMS1 expression in patients with dilated cardiomyopathy and murine cardiomyocytes, suggesting that LIMS1 dysregulation contributes to cardiac pathology. Using CRISPR/Cas9 technology, we generate a zebrafish model of lims1 loss-of-function mutant, which exhibits severe cardiac chamber remodeling, systolic dysfunction, and premature mortality, demonstrating the essential role of lims1 in maintaining cardiac integrity. Transcriptomic profiling reveals the activation of the gp130/Jak1/Stat3 signaling in the lims1-deficient hearts. Strikingly, pharmacological inhibition of Stat3 or c-Fos partially rescues cardiomyopathy phenotypes. Our findings reveal the underlying mechanism of lims1 deficiency-caused heart failure through gp130/Jak1/Stat3 hyperactivation, offering insights into cardiac remodeling and potential therapeutic strategies.

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来源期刊
Journal of Genetics and Genomics
Journal of Genetics and Genomics 生物-生化与分子生物学
CiteScore
8.20
自引率
3.40%
发文量
4756
审稿时长
14 days
期刊介绍: The Journal of Genetics and Genomics (JGG, formerly known as Acta Genetica Sinica ) is an international journal publishing peer-reviewed articles of novel and significant discoveries in the fields of genetics and genomics. Topics of particular interest include but are not limited to molecular genetics, developmental genetics, cytogenetics, epigenetics, medical genetics, population and evolutionary genetics, genomics and functional genomics as well as bioinformatics and computational biology.
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