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.
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.