Ao Lihua, Zhai Yufeng, Jin Chunhua, Cleveland Joseph C, Fullerton David A, Meng Xianzhong
Departments of Surgery, University of Colorado Denver, Aurora, Colorado.
Mol Med. 2017 Jan;23:863-872. doi: 10.2119/molmed.2016.00204. Epub 2016 Dec 19.
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 post-ischemic 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 global I/R. Augmented release of HSP27 in aging hearts is associated with greater production of cytokines (TNF-α and IL-1β) 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-κB 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 post-ischemic functional recovery in aging hearts is due, at least in part, to augmented myocardial release of HSP27 and elevated myocardial TLR4 levels.
在经历强制性全心肌缺血/再灌注（I/R）的心脏手术后，老年人的心脏功能恢复会减弱，但其潜在机制仍未完全明确。我们之前观察到，在全心I/R期间，人和小鼠的心肌会释放热休克蛋白（HSP）27。细胞外HSP27会诱导心肌炎症反应，并在成年小鼠心脏的缺血后心脏功能障碍中发挥作用。
本研究旨在确定细胞外HSP27和Toll样受体4（TLR4）在老年小鼠心脏全心I/R后功能恢复减弱中的作用。
分离出老年（18 - 24个月）和成年（4 - 6个月）小鼠的心脏，进行全心I/R。老年心脏中HSP27释放增加与细胞因子（TNF-α和IL-1β）产生增多以及功能恢复较差相关。抗HSP27抑制了炎症反应，并显著改善了老年心脏的功能恢复。与成年心脏相比，向老年心脏灌注重组HSP27会导致细胞因子产生增多和收缩功能抑制更严重。TLR4缺陷消除了暴露于重组HSP27的老年心脏中的细胞因子产生和功能损伤。有趣的是，老年心脏的TLR4蛋白水平较高，并且在HSP27刺激或I/R后显示出增强的TLR4介导的NF-κB激活。
细胞外HSP27和TLR4共同增强炎症反应，并阻碍老年心脏I/R后的功能恢复。老年心脏对全心I/R的炎症反应增强和缺血后功能恢复减弱至少部分归因于心肌HSP27释放增加和心肌TLR4水平升高。
