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达帕格利弗洛辛通过对抗介素-11受体亚单元α来干扰纤维细胞中的亲纤维炎性介素11-纳辛C相互强化

Yen-Chen Lin^1,2, Wei-Jan Chen^2,3, Yu-Juei Hsu^4,5

¹Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.

Journal of cellular physiology

|June 30, 2025

概括

像达帕格利弗洛辛这样的/葡萄糖共运输体2抑制剂 (SGLT2i) 通过阻断IL11-TNC纤维炎循环来保护心脏. 这项研究揭示了IL11和tenascin-C (TNC) 如何相互作用以促进心脏纤维化,以及SGLT2i如何破坏这种途径.

科学领域:

心血管研究研究心血管研究
分子生物学分子生物学
药理学药理学是指药理学的学科.

背景情况:

/葡萄糖共运输体2抑制剂 (SGLT2i) 显示出心脏保护作用,但其机制尚不清楚.
针对血小板缺血的INTERLEUKIN-11 (IL11) 治疗可能会诱导心力衰竭,这与益菌细胞外基质 (ECM) 蛋白升调有关.
素-C (TNC) 是一种ECM蛋白质,作为一种促炎性警示剂,可能调解IL11诱导的心脏损伤.

研究的目的:

为了研究IL11对TNC的升级调节,通过Toll-like受体4 (TLR4) 诱导纤维炎症,以及SGLT2i达帕格利弗洛辛对抗这些效应的假设.
阐明NADPH氧化酶2 (NOX2) 和ERK信号在IL11-TNC-TLR4通路中的作用.
提出一种IL11-TNC信号传递在心脏纤维细胞中的模型,并通过dapagliflozin进行其调制.

主要方法:

用IL11和TNC进行纤维细胞刺激,然后用TLR4抑制剂 (TLR4i),NOX2抑制剂 (NOX2i) 和中和IL11抗体进行治疗.
对ECM蛋白和ERK酸化的评估.
分子对接,光灭和IL11信号抑制剂尾酒,以研究达帕格利弗洛辛对IL11受体亚单元α (IL11RA) 的作用机制.

主要成果:

IL11刺激调高了TNC,创建了一个涉及ERK信号的TNC-TLR4-NOX2自动放大循环.
此外,TNC刺激也提高了IL11的调节,证实了纤维细胞中IL11-ERK和TNC-TLR4-NOX2通路之间的相互强化循环.
达帕格利弗洛辛通过对抗IL11RA.有效地预防了IL11或TNC诱导的纤维炎症.

结论:

IL11,TNC,TLR4,NOX2和ERK在纤维细胞中相互依赖,形成一个积极的反循环,维持心脏纤维炎症.
作为IL11和TNC的主要生产者,激活的纤维细胞对心脏纤维炎症微环境的支持至关重要.
达帕格利弗洛辛通过对抗IL11RA来中断人类心脏纤维细胞中的IL11-TNC相互增强,为心力衰竭提供了潜在的治疗策略.

关键词:

在NADPH氧化酶.这是一种SGLT2抑制剂.收费类受体4 收费类受体纤维化纤维化这是一种炎症炎症炎症炎症.介质蛋白-111 介质蛋白-111 在纳辛C C 的使用.

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