Cardiomyopathy commonly occurs after sepsis and is closely associated with high mortality in clinic. Interferon regulatory factor-2 binding protein 2 (IRF2BP2) has been identified as a negative regulator of inflammation, but its role in septic cardiomyopathy is unknown. The current study aims to illuminate the regulatory function of IRF2BP2 on sepsis-induced cardiomyopathy and to explore the underlying mechanisms. Protein expression of IRF2BP2 in response to sepsis-induced cardiomyopathy was examined in the heart of mice challenged by LPS intraperitoneal injection. AAV9-delivered IRF2BP2 overexpression in the heart was applied to evaluate the regulatory role of IRF2BP2 in sepsis-induced myocardial depression, inflammatory response, and cell death. The molecular mechanisms underlying IRF2BP2-regulated cardiomyopathy were explored using western blot screening assay. Primary cardiomyocytes have been isolated to further confirm the role and mechanism of IRF2BP2 during septic cardiomyopathy. IRF2BP2 expression was dramatically increased in the heart of mice after LPS administration. AAV9-mediated IRF2BP2 overexpression significantly improved sepsis-induced cardiac dysfunction, inhibited inflammatory cell infiltration and cytokine production, and blocked cell death after LPS treatment. Mechanistically, IRF2BP2 activated AMPK signaling in cardiomyocytes, while inhibiting AMPK activation largely reversed IRF2BP2-benefited inflammatory suppression and cell survival. These findings clearly demonstrated that IRF2BP2 is a potent suppressor of sepsis-induced myocardial depression and related heart impairment. Targeting IRF2BP2 represents a promising therapeutic strategy for septic cardiomyopathy.

心肌病通常发生在败血症后，并且与临床上的高死亡率密切相关。干扰素调节因子 2 结合蛋白 2 (IRF2BP2) 已被确定为炎症的负调节因子，但其在脓毒性心肌病中的作用尚不清楚。本研究旨在阐明 IRF2BP2 对脓毒症诱导的心肌病的调节作用并探索其潜在机制。在受到 LPS 腹腔注射攻击的小鼠心脏中检测了 IRF2BP2 响应败血症诱导的心肌病的蛋白质表达。应用 AAV9 传递的 IRF2BP2 在心脏中过表达来评估 IRF2BP2 在脓毒症诱导的心肌抑制、炎症反应和细胞死亡中的调节作用。使用蛋白质印迹筛选试验探索了 IRF2BP2 调节的心肌病的分子机制。已分离出原代心肌细胞以进一步证实 IRF2BP2 在脓毒性心肌病中的作用和机制。LPS 给药后，小鼠心脏中 IRF2BP2 的表达显着增加。AAV9 介导的 IRF2BP2 过表达显着改善了脓毒症引起的心脏功能障碍，抑制了炎症细胞浸润和细胞因子的产生，并在 LPS 治疗后阻止了细胞死亡。从机制上讲，IRF2BP2 激活心肌细胞中的 AMPK 信号传导，而抑制 AMPK 激活在很大程度上逆转了 IRF2BP2 受益的炎症抑制和细胞存活。这些发现清楚地表明 IRF2BP2 是脓毒症引起的心肌抑制和相关心脏损伤的有效抑制因子。靶向 IRF2BP2 代表了一种有前途的脓毒性心肌病治疗策略。