Mechanisms of cardiac dysfunction in sepsis

项目摘要 老年患者在脓毒症时极易发生心功能不全。然而，机制 老年人心功能不全风险增加的根本原因尚不清楚。计划中的研究 该项目将检验心脏中与衰老相关的Klotho缺乏症和TLR 2过度表达的假设。 增加心肌对脓毒症的炎症反应，从而加重心脏功能障碍。 这一假说基于以下新发现：（1）衰老加剧了心肌/全身性 内毒素血症或脓毒症引起的炎症反应和心功能障碍;（2）高 衰老心脏的炎性表型的特征在于升高的组成性炎症、Klotho缺乏 （3）TLR 2在介导炎症反应、心肌细胞凋亡、心肌细胞凋亡中起重要作用。 （4）重组Klotho能够抑制TLR 2的表达 （5）抗炎细胞因子IL-37增加 心肌Klotho水平，并在保护老年脓毒症小鼠的心脏功能。 本课题的主要目的是阐明衰老对心肌细胞的影响机制， Klotho和TLR 2的表达，并确定Klotho缺陷和TLR 2过表达在肿瘤发生中的作用。 老年脓毒症心肌炎症反应及心功能不全的机制 小鼠我们将追求以下相互关联的具体目标：（1）检验Klotho缺乏症的假设， 在衰老相关的心肌过度炎症和脓毒症心功能不全中起重要作用;（2） 验证衰老心脏中较低的Klotho水平促进TLR 2表达的假设;（3）探索衰老心脏中的TLR 2表达水平。 抗炎细胞因子IL-37在脓毒症中用于器官保护的治疗潜力。 计划中的研究将深入了解 并为开发创新策略提供基础，以保护衰老的心脏免受感染 由败血症引起的功能障碍。

PROJECT SUMMARY Elderly patients are highly vulnerable to cardiac dysfunction while in sepsis. However, the mechanism underlying the increased risk of cardiac dysfunction in the elderly is poorly understood. Planned studies in this project will test the hypothesis that aging-related Klotho deficiency and TLR2 overexpression in the heart augment the myocardial inflammatory responses to sepsis and thereby exacerbate cardiac dysfunction. This hypothesis rests on the following novel findings: (1) aging exacerbates the myocardial/systemic inflammatory responses and cardiac dysfunction caused by either endotoxemia or sepsis; (2) the hyper- inflammatory phenotype of aging heart is characterized by elevated constitutive inflammation, Klotho deficiency and TLR2 overexpression; (3) TLR2 has a critical role in mediating the inflammatory responses, cardiac dysfunction and mortality in old septic mice; (4) recombinant Klotho is capable of suppressing TLR2 expression in aging heart and improving cardiac function in old septic mice; (5) anti-inflammatory cytokine IL-37 increases myocardial Klotho levels and is potent in protecting cardiac function in old septic mice. The major goals of this project are to elucidate the mechanism by which aging exerts an impact on myocardial expression of Klotho and TLR2, and to determine the role of Klotho deficiency and TLR2 overexpression in the mechanism underlying myocardial inflammatory responses and cardiac dysfunction caused by sepsis in old mice. We will pursue the following interrelated Specific Aims: (1) to test the hypothesis that Klotho deficiency plays an important role in aging-related myocardial hyper-inflammation and cardiac dysfunction in sepsis; (2) to test the hypothesis that lower Klotho levels in aging heart promote TLR2 expression; (3) to explore the therapeutic potential of anti-inflammatory cytokine IL-37 for organ protection in sepsis. The planned studies will provide insights into the mechanisms underlying the hyper-inflammatory responses of aging heart to infection and offer the basis for developing innovative strategies to protect aging heart against dysfunction caused by sepsis.