权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Inflammatory response of aging heart to surgical myocardial ischemia

衰老心脏对手术心肌缺血的炎症反应

基本信息

批准号：
8882208
负责人：
XIANZHONG MENG
金额：
$ 30万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8882208
关键词：
Acidosis Adhesions Aging Antibodies Blood C-terminal Calcium Cardiac Cardiac Myocytes Cardiac Surgery procedures Cardiopulmonary Bypass Cell Aging Cells Coronary Elderly Endothelial Cells Exhibits Extracellular Domain Generations Goals HSPB1 gene Heart Heart Transplantation Heat Shock Protein 27 Human Hypoxia Infiltration Inflammation Mediators Inflammatory Inflammatory Response Injury Interleukin-1 Ischemia Lead Low Cardiac Output Syndrome Mediating Membrane Microdomains Minor Modeling Mononuclear Mus Myocardial Myocardial Ischemia Myocardial Reperfusion Myocardial dysfunction Myocardial tissue Myocardium Operative Surgical Procedures Outcome Peptides Phosphorylation Production Reactive Oxygen Species Recombinants Recovery of Function Reperfusion Injury Reperfusion Therapy Rest Risk Role Signal Transduction Stress TLR4 gene Testing Therapeutic Toll-Like Receptor 2 Vascular blood supply age effect age related base cell age cytokine extracellular improved innovation insight new therapeutic target novel older patient response therapeutic target thermal stress

项目摘要

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.

描述（由申请人提供）：老年患者在心脏手术后容易出现低心输出量综合征，导致全脑心肌缺血和再灌注（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。本研究将验证以下假设：衰老增强冠状动脉内皮对缺氧/热应激的反应，导致热休克蛋白27（HSP 27，小鼠HSP 25）分泌增加，以及细胞外HSP 27作为Toll样受体2（TLR 2）和TLR 4的激活剂发挥作用，从而增强衰老心脏缺血后损伤。结论：1）老年人和小鼠心肌缺血再灌注后产生更多的促炎介质，与HSP 27/25的释放有关; 2）冠状动脉内皮细胞在缺氧时释放HSP 27/25，且随着心肌缺血再灌注时间的延长，心肌缺血再灌注后HSP 27/25的释放增加; 3）拮抗细胞外HSP 25抑制炎症反应并改善衰老小鼠心脏的心功能恢复，4）细胞外HSP 27/25通过依赖于TLR 2和TLR 4的机制诱导心肌和心脏细胞中的炎症反应，5）HSP 27/25的C-末端结构域是其促炎作用的关键。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分泌HSP 27/25的影响，细胞外HSP 25在衰老心脏手术全脑I/R后高炎症反应中的作用，阐明细胞外HSP 27/25诱导心肌炎症反应的机制。我们将努力实现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低氧和低温应激的反应以分泌HSP 27/25的假设，2）确定细胞外HSP 27/25在衰老心脏中TLR 2/4介导的心肌炎症反应中的作用，3）验证细胞外HSP 27/25的C端结构域激活TLR 2和TLR 4的假设; 4）探索拮抗细胞外HSP 27/25和TLR 2/4的治疗潜力。拟议的研究将为老龄心脏对手术全局I/R的高度炎症反应的机制提供新的见解，并为开发创新策略以在强制性全局I/R的心脏手术期间保护老龄心脏提供基础。