IκBζ promotes acute myocardial infarction via endonuclear STAT3 deactivation

IF 4.2 3区 医学 Q1 PHARMACOLOGY & PHARMACY
Tong Zhou , Hong Hong , Lu Zhang , Yang Qiao , Yuan Jiang , Ximing Chen , Zheng Dong , Bo Zhang , Mingyu Zhang , Chaoqian Xu , Rong Zhang
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引用次数: 0

Abstract

The protein IkappaB-Zeta (IκBζ), which is a member of the IkappaB (IκB) family, has been implicated in the onset and progression of immune-mediated inflammation and cancer. However, its role in cardiovascular disease remains totally unexplored. We employed advanced molecular techniques to investigate the upregulation of IκBζ protein in mouse models of acute myocardial infarction (AMI) and cellular oxygen-glucose deprivation (OGD), with a focus on nuclear localization. Our results indicate that inhibiting IκBζ protein expression both in vivo and in vitro can reduce cardiomyocyte apoptosis and alleviate cardiac hypoxic injury. Mechanistically, IκBζ influences cardiomyocyte apoptosis by binding to and regulating the activity of the intracellular signal transduction factor and transcriptional activator (STAT3). Upon AMI occurrence, the janus kinase 2-signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway is activated, leading to STAT3 phosphorylation and its subsequent translocation into the nucleus. It interacts with activated IκBζ in the nucleus, resulting in decreased STAT3 activity and exacerbating cardiomyocyte apoptosis. Treatment with a STAT3-specific agonist mitigated the pro-apoptotic effects caused by IκBζ overexpression. In conclusion, our study describes for the first time the molecular link in IκBζ and STAT3 and reveals that pro-apoptotic IκBζ plays a crucial role in AMI pathogenesis by downregulating STAT3 activity. These findings suggest that targeting IκBζ may provide a foundation for developing novel therapeutic strategies for the prevention and treatment of myocardial infarction.
κ b ζ通过核内STAT3失活促进急性心肌梗死。
ikapab - zeta (IκBζ)蛋白是ikapab (IκB)家族的成员,与免疫介导的炎症和癌症的发生和进展有关。然而,它在心血管疾病中的作用仍然完全未被探索。我们采用先进的分子技术研究了IκBζ蛋白在小鼠急性心肌梗死(AMI)和细胞氧-葡萄糖剥夺(OGD)模型中的上调,重点研究了核定位。结果表明,抑制IκBζ蛋白在体内和体外的表达均可减少心肌细胞凋亡,减轻心脏缺氧损伤。在机制上,IκBζ通过结合和调节细胞内信号转导因子和转录激活因子(STAT3)的活性来影响心肌细胞凋亡。AMI发生后,janus kinase 2-signal transducer and activator of transcription 3 (JAK2/STAT3)信号通路被激活,导致STAT3磷酸化并随后易位进入细胞核。它与细胞核中活化的IκBζ相互作用,导致STAT3活性降低,加剧心肌细胞凋亡。用stat3特异性激动剂治疗可减轻IκBζ过表达引起的促凋亡作用。总之,我们的研究首次描述了IκBζ和STAT3之间的分子联系,揭示了促凋亡的IκBζ通过下调STAT3活性在AMI发病过程中起着至关重要的作用。这些发现表明,靶向IκBζ可能为开发预防和治疗心肌梗死的新治疗策略提供基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
9.00
自引率
0.00%
发文量
572
审稿时长
34 days
期刊介绍: The European Journal of Pharmacology publishes research papers covering all aspects of experimental pharmacology with focus on the mechanism of action of structurally identified compounds affecting biological systems. The scope includes: Behavioural pharmacology Neuropharmacology and analgesia Cardiovascular pharmacology Pulmonary, gastrointestinal and urogenital pharmacology Endocrine pharmacology Immunopharmacology and inflammation Molecular and cellular pharmacology Regenerative pharmacology Biologicals and biotherapeutics Translational pharmacology Nutriceutical pharmacology.
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