Attenuated Recovery of Contractile Function in Aging Hearts Following Global Ischemia/Reperfusion: Role of Extracellular HSP27 and TLR4
Attenuated Recovery of Contractile Function in Aging Hearts Following Global Ischemia/Reperfusion: Role of Extracellular HSP27 and TLR4
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DOI：
10.2119/molmed.2016.00204
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发表时间：
2016-01-01
影响因子：
5.7
通讯作者：
Meng, Xianzhong
中科院分区：
文献类型：
--
作者：
Ao, Lihua;Zhai, Yufeng;Meng, Xianzhong
虽然老年人心脏手术后强制性心肌缺血/再灌注（I/R）的心脏功能恢复减弱，但其潜在机制仍不完全清楚。我们以前观察到，人类和小鼠心肌释放热休克蛋白（HSP）27在全球I/R。细胞外热休克蛋白27诱导成年小鼠心肌炎症反应并在缺血后心功能不全中发挥作用本研究旨在探讨细胞外热休克蛋白27（HSP 27）和Toll样受体4（TLR 4）在老龄小鼠全脑缺血再灌注（I/R）后心脏功能恢复减弱中的作用。对从老化（18-24个月）和成年（4-6个月）小鼠分离的心脏进行离体整体I/R。在衰老的心脏中，HSP 27的释放增加与细胞因子（TNF-α和IL-1 β）的产生增加和功能恢复不良有关。抗HSP 27抑制炎症反应，并显着改善老化心脏的功能恢复。与成人心脏相比，向老化心脏灌注重组HSP 27导致更大的细胞因子产生和更严重的收缩抑制。TLR 4缺乏可抑制重组HSP 27诱导的衰老心脏细胞因子的产生和功能损伤。有趣的是，衰老的心脏有更高的TLR 4蛋白水平，并且在HSP 27刺激或I/R后显示增强的TLR 4介导的NF-κ B活化。细胞外HSP 27和TLR 4共同增强衰老心脏I/R后的炎症反应并阻碍功能恢复。老年心脏对整体I/R的炎症反应增强和缺血后功能恢复减弱至少部分是由于心肌HSP 27释放增加和心肌TLR 4水平升高。
While cardiac functional recovery is attenuated in the elderly following cardiac surgery with obligatory global myocardial ischemia/reperfusion (I/R), the underlying mechanism remains incompletely understood. We observed previously that human and mouse myocardium releases heat shock protein (HSP) 27 during global I/R. Extracellular HSP27 induces myocardial inflammatory response and plays a role in postischemic cardiac dysfunction in adult mouse hearts. This study was to determine the role of extracellular HSP27 and Toll-like receptor 4 (TLR4) in the attenuated functional recovery in aging mouse hearts following global I/R. Hearts isolated from aging (18-24 months) and adult (4-6 months) mice were subjected to ex vivo global I/R. Augmented release of HSP27 in aging hearts was associated with greater production of cytokines (TNF-alpha and IL-1 beta) and worse functional recovery. Anti-HSP27 suppressed the inflammatory response and markedly improved functional recovery in aging hearts. Perfusion of recombinant HSP27 to aging hearts resulted in greater cytokine production and more severe contractile depression in comparison to adult hearts. TLR4 deficiency abolished cytokine production and functional injury in aging hearts exposed to recombinant HSP27. Interestingly, aging hearts had higher TLR4 protein levels and displayed enhanced TLR4-mediated NF-kappa B activation following HSP27 stimulation or I/R. Extracellular HSP27 and TLR4 jointly enhance the inflammatory response and hamper functional recovery following I/R in aging hearts. The enhanced inflammatory response to global I/R and attenuated postischemic functional recovery in aging hearts are due, at least in part, to augmented myocardial release of HSP27 and elevated myocardial TLR4 levels.