Inflammatory response of aging heart to surgical myocardial ischemia

描述(申请人提供)：老年患者在心脏手术后易患低心排血量综合征，导致全心缺血和再灌流(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。这一方案中的研究将检验以下假设：衰老增强冠状动脉内皮细胞对低氧/热应激的反应，导致热休克蛋白27(HSP27，在小鼠中的HSP25)分泌增加，以及细胞外HSP27作为Toll样受体2(TLR2)和TLR4的激活物，从而增加老龄心脏缺血后的损伤。这些假说基于下列新的发现：1)在衰老的人和小鼠的心脏，全球I/R后产生更多的促炎介质，与HSP27/25的大量释放相关，2)冠状动脉内皮细胞对低氧做出反应，释放HSP27/25，而衰老心脏的内皮细胞则增加HSP27/25的释放；3)拮抗细胞外HSP25抑制炎症反应，促进衰老小鼠心脏功能的恢复；4)细胞外HSP27/25通过依赖TLR2和TLR4的机制诱导心肌和心脏细胞内的炎症反应；5)HSP27/25的C末端结构域对于其促炎作用至关重要。本研究的主要目的是进一步探讨衰老对冠状动脉内皮细胞HSP27/25分泌机制的影响，以及细胞外HSP25在老年心脏外科手术后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。我们将追求以下相关的具体目标：1)检验衰老增强冠状动脉内皮细胞对低氧和低温应激分泌HSP27/25的反应的假说；2)确定细胞外HSP27/25在TLR2/4介导的衰老心脏心肌炎性反应中的作用。3)验证细胞外HSP27/25的C-末端结构域激活TLR2和TLR4的假说；4)探讨拮抗细胞外HSP27/25和TLR2/4的治疗潜力。本研究将为研究心脏外科手术中高炎症反应的机制以及在心脏手术中保护老年心脏的创新策略提供依据。 公共卫生相关性：心脏手术后心脏供血暂停的老年患者易患低心排血量综合征。目前，原因尚不清楚。这项建议中的研究将确定心肌炎性反应在与年龄相关的术后不良结果中的作用。拟议的研究将确定心脏手术期间保护老化心脏的潜在治疗靶点。

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. PUBLIC HEALTH RELEVANCE: The elderly patients are vulnerable to low cardiac output syndrome after heart surgery with temporary cessation of blood supply to the heart. Currently, the reason for this is unclear. Studies in this proposal will determine the role of myocardial inflammatory responses in the worse post-surgery outcome associated with aging. The proposed studies will identify potential therapeutic targets for protection of aging heart during cardiac surgery.