Pleiotropic Role of TNIK in Sepsis-Induced Cardiomyopathy

IF 4.5 2区生物学 Q2 CELL BIOLOGY

Journal of Cellular Physiology Pub Date : 2025-04-03 DOI:10.1002/jcp.70027

Wenwen Yang, Aizhen Zhao, Wangrui Lei, Junmin Chen, Huanle Yan, Jiawen Li, Yang Yang, Ying Chen

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Abstract

Heart failure induced by sepsis is considered one of the foremost contributors to mortality in intensive care unit (ICU) patients. However, the molecular mechanism of myocardial damage in sepsis has not been fully elucidated at present. TNF receptor-associated factor-2 and Nck-interacting protein kinase (TNIK) are members of the germinal center kinase superfamily. TNIK exhibits a pivotal role as a conserved modulator of glucose and lipid homeostasis. Here, we aimed to investigate the potential direct roles of TNIK and whether TNIK exerts anti-septic myocardial damage by regulating the NLRP3 pathway. We initially revealed that TNIK was the crucial involvement of septic myocardial injury. Subsequently, we constructed a cecal ligation and puncture (CLP) mouse model and employed LPS-induced injury in HL-1 cardiomyocytes. Our observations revealed an upregulation of TNIK levels in both CLP-injured mice and LPS-treated HL-1 cells. However, TNIK inhibitor TNIK-IN-7 or siRNA attenuated cardiomyocyte LPS injury. Especially, TNIK siRNA can significantly downregulate TNIK as well as decrease NLRP3 and IL-1β mRNA and protein levels, though the explicit molecular mechanisms of TNIK-NLRP3 in septic myocardial require further investigation. Together, our investigation presents novel evidence suggesting TNIK as a potential therapeutic target for the prevention and therapeutic intervention in sepsis-induced cardiomyopathy.

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TNIK在败血症性心肌病中的多效性作用

脓毒症引起的心力衰竭被认为是重症监护病房（ICU）患者死亡的主要原因之一。然而，脓毒症心肌损伤的分子机制目前尚未完全阐明。TNF受体相关因子-2和nck相互作用蛋白激酶（TNIK）是生发中心激酶超家族的成员。TNIK作为葡萄糖和脂质稳态的保守调节剂发挥着关键作用。在这里，我们旨在研究TNIK的潜在直接作用，以及TNIK是否通过调节NLRP3途径施加抗脓毒性心肌损伤。我们最初发现TNIK是脓毒性心肌损伤的关键累及。随后，我们建立了盲肠结扎穿刺（CLP）小鼠模型，并采用lps诱导HL-1心肌细胞损伤。我们的观察结果显示，clp损伤小鼠和lps处理的HL-1细胞中TNIK水平均上调。然而，TNIK抑制剂TNIK- in -7或siRNA可减轻心肌细胞LPS损伤。特别是，TNIK siRNA可以显著下调TNIK，降低NLRP3和IL-1β mRNA和蛋白水平，但TNIK-NLRP3在脓毒症心肌中的明确分子机制有待进一步研究。总之，我们的研究提供了新的证据，表明TNIK是预防和治疗脓毒症引起的心肌病的潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Cellular Physiology 生物-生理学

CiteScore

14.70

自引率

0.00%

发文量

256

审稿时长

1 months

期刊介绍： The Journal of Cellular Physiology publishes reports of high biological significance in areas of eukaryotic cell biology and physiology, focusing on those articles that adopt a molecular mechanistic approach to investigate cell structure and function. There is appreciation for the application of cellular, biochemical, molecular and in vivo genetic approaches, as well as the power of genomics, proteomics, bioinformatics and systems biology. In particular, the Journal encourages submission of high-interest papers investigating the genetic and epigenetic regulation of proliferation and phenotype as well as cell fate and lineage commitment by growth factors, cytokines and their cognate receptors and signal transduction pathways that influence the expression, integration and activities of these physiological mediators. Similarly, the Journal encourages submission of manuscripts exploring the regulation of growth and differentiation by cell adhesion molecules in addition to the interplay between these processes and those induced by growth factors and cytokines. Studies on the genes and processes that regulate cell cycle progression and phase transition in eukaryotic cells, and the mechanisms that determine whether cells enter quiescence, proliferate or undergo apoptosis are also welcomed. Submission of papers that address contributions of the extracellular matrix to cellular phenotypes and physiological control as well as regulatory mechanisms governing fertilization, embryogenesis, gametogenesis, cell fate, lineage commitment, differentiation, development and dynamic parameters of cell motility are encouraged. Finally, the investigation of stem cells and changes that differentiate cancer cells from normal cells including studies on the properties and functions of oncogenes and tumor suppressor genes will remain as one of the major interests of the Journal.