Inflammatory response of aging heart to surgical myocardial ischemia

描述（由申请人提供）：老年患者在心脏手术后易发生低心输出量综合征，导致全身心肌缺血再灌注（I/R）。然而，老年人心肌功能损伤风险增加的机制尚不完全清楚。本研究将验证衰老增强冠状动脉内皮对缺氧/热应激的反应，导致小鼠热休克蛋白27 （HSP27, HSP25）的分泌增加，以及细胞外HSP27作为toll样受体2 （TLR2）和TLR4的激活剂，从而增加衰老心脏缺血后损伤的假设。这些假设基于以下新发现：1)在衰老的人和小鼠中，心脏在全局I/R后产生更多的促炎介质，这与HSP27/25的释放增加有关；2)冠状动脉内皮细胞释放HSP27/25以响应缺氧，并且在衰老的心脏内皮细胞中释放增加；3)拮抗细胞外HSP25抑制衰老小鼠心脏的炎症反应，促进心功能恢复；4)细胞外HSP27/25诱导心肌和心肌细胞的炎症反应，其机制依赖于TLR2和TLR4； 5) HSP27/25的c端结构域对其促炎作用至关重要。本研究的主要目的是进一步确定衰老对冠状动脉内皮细胞分泌HSP27/25的影响机制，细胞外HSP25在介导衰老心脏手术全局I/R的高炎症反应中的作用，并阐明细胞外HSP27/25诱导心肌炎症反应的机制。我们将追求以下相互关联的具体目标：1)验证衰老增强冠状动脉内皮对缺氧和低温应激的反应以促进HSP27/25分泌的假说，2)确定细胞外HSP27/25在衰老心脏TLR2/4介导的心肌炎症反应中的作用，3)验证细胞外HSP27/25 c -末端结构域激活TLR2和TLR4的假说，4)探索拮抗细胞外HSP27/25和TLR2/4的治疗潜力。拟议的研究将为衰老心脏对手术整体I/R的高炎症反应机制提供新的见解，并为制定创新策略提供基础，以保护心脏手术期间强制性整体I/R的老化心脏。

DESCRIPTION (provided by applicant): Elderly patients are vulnerable to low cardiac output syndrome after cardiac surgery that obligates global myocardial ischemia and reperfusion (I/R). However, the mechanisms underlying the increased risk of myocardial functional injury in the elderly are incompletely understood. Studies in this proposal will test the hypotheses that aging enhances coronary endothelial response to hypoxic/thermal stress, resulting in augmented secretion of heat shock protein 27 (HSP27, HSP25 in mice), and that extracellular HSP27 functions as an activator of Toll-like receptor 2 (TLR2) and TLR4, and thereby augments post-ischemic injury in aging heart. The hypotheses rest on the following novel findings: 1) in aging humans and mice, heart produces more pro-inflammatory mediators after global I/R that correlate with a greater release of HSP27/25, 2) coronary endothelial cells release HSP27/25 in response to hypoxia, and the release is augmented in endothelial cells from aging hearts; 3) antagonizing extracellular HSP25 suppresses the inflammatory response and improves cardiac functional recovery in aging murine hearts, 4) extracellular HSP27/25 induces the inflammatory response in the myocardium and cardiac cells through a mechanism dependent of both TLR2 and TLR4, and 5) the C-terminal domain of HSP27/25 is critical for its pro-inflammatory effects. The major goals of this proposal are to further determine the effect of aging on the mechanisms of coronary endothelial secretion of HSP27/25, the role of extracellular HSP25 in mediating the hyper-inflammatory response to surgical global I/R in aging hearts, and to elucidate the mechanism by which extracellular HSP27/25 induces the myocardial inflammatory response. We will pursue the following interrelated specific aims: 1) to test the hypothesis that aging augments coronary endothelial response to hypoxic and hypothermic stress for secretion of HSP27/25, 2) to determine the role of extracellular HSP27/25 in the TLR2/4-mediated myocardial inflammatory response in aging hearts, 3) to test the hypothesis that the C-terminal domain of extracellular HSP27/25 activates TLR2 and TLR4 and 4) to explore the therapeutic potential of antagonizing extracellular HSP27/25 and TLR2/4. The proposed studies will provide novel insights into the mechanisms underlying the hyper-inflammatory response of aging heart to surgical global I/R and the basis for developing innovative strategies to protect aging heart during cardiac surgery with obligatory global I/R.