Tsg101 and endosomes in cardiac surgery-induced injury

Tsg101 和内体在心脏手术引起的损伤中的作用

• 批准号: 10066356
• 负责人: Guo-Chang Fan
• 金额: $ 30.5万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-10 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10066356
• 关键词: Acceleration; Address; Adult; Anaerobic Bacteria; Animals; Antibiotics; Binding; Bone Marrow Stem Cell; Cardiac; Cardiac Myocytes; Cardiac Surgery procedures; Cell Survival; Cessation of life; Clinical Trials; Complex; Coronary Artery Bypass; Data; Endosomes; Energy-Generating Resources; Family; Fatty Acids; Generations; Genes; Glucose; Glucose Transporter; Glycogen; Glycolysis; Heart; Heart Injuries; Human; Hypoxia; Impairment; Infarction; Infusion procedures; Injections; Injury; Insulin; Insulin Resistance; Ischemia; Knowledge; Lentivirus Vector; Measures; Mediating; Membrane; Membrane Proteins; Mesenchymal Stem Cells; Mission; Mitochondria; Morbidity - disease rate; Mus; Muscle Cells; Myocardial; Myocardial Ischemia; Operative Surgical Procedures; Outcome; Oxygen Consumption; Pathway interactions; Patients; Play; Postoperative Period; Potassium; Production; Protein Isoforms; Proteins; Public Health; Recombinants; Recovery of Function; Recycling; Regulation; Reperfusion Injury; Reperfusion Therapy; Research; Role; Sarcolemma; Sorting - Cell Movement; Source; Stress; Surface; TSG101 gene; Testing; Therapeutic; Translating; Transplantation; United States National Institutes of Health; Up-Regulation; Work; anaerobic glycolysis; attenuation; base; cardioprotection; disability; exosome; glucose uptake; heart damage; improved; in vivo; knock-down; mortality; mouse model; nanovesicle; novel; overexpression; oxidation; pre-clinical; prevent; protective effect; receptor; recruit; small hairpin RNA; tool; translational study

Heart surgery for both coronary artery bypass graft (CABG) and transplantation often involves cardiac ischemia/reperfusion (I/R), which leads to a switch of the myocardial energy source from fatty acid β- oxidation to anaerobic glycolysis. As an adaptation, Glut-4, a major isoform of the glucose transporters in the heart, is recruited to the cardiomyocyte surface (also called sarcolemma) to take up glucose and stimulate cardiac ATP production. Nonetheless, such compensatory Glut4 translocation is not sufficient to meet cardiac glucose demands for ATP generation in I/R hearts and thereby, results in an energy crisis. Notably, recent multiple large clinical trials involving infusion of glucose-insulin-potassium (GIK) solution into patients undergoing cardiac surgery have not shown any positive results (or even worse). Therefore, exploring how to augment Glut-4 translocation and glucose utilization, independent of insulin, is desperately needed to counter I/R-triggered cardiac energy loss. We recently made the novel findings that the tumor susceptibility gene 101 (Tsg101), a central component of the ESCRT (endosomal sorting complexes required for transport) machinery, is able to regulate the endosomal recycling of membrane receptors in animal hearts. Our newest data further showed that: 1) Tsg101 binds directly to Glut-4 in adult mouse hearts; 2) forced expression of Tsg101 in cultured myocytes resulted in higher levels of sarcolemma Glut-4 and improved cell survival when challenged with hypoxia/reoxygenation; and 3) Tsg101 up-regulates the expression of Rab11a and FIP3 (Rab11-family interacting protein 3), two key factors involved in endosomal recycling. Most importantly, our pilot data also showed that a group of naturally-occurring nano-vesicles, exosomes, released by bone- marrow stem cells, can effectively deliver Tsg101 into cardiac myocytes. Based on these initial findings, we hypothesize that Tsg101 can reduce or prevent cardiac I/R-induced energy crisis/injury by promoting Rab11a/ FIP3-mediated endosomal recycling of Glut-4. Treatment of mouse hearts with Tsg101-containing exosomes before ischemia or during early reperfusion can elevate myocardial Tsg101, thereby limiting I/R-triggered cardiac damage. The work proposed here will address three specific aims: 1) Define the role of Tsg101 in glucose-dependent energy generation and cardio-protection from I/R injury, using both heart-specific Tsg101-overexpressing and inducible knockdown mouse models; 2) Identify whether Tsg101-induced cardio-protection is dependent on Rab11a/FIP3-mediated endosomal recycling of Glut-4; and 3) Investigate the therapeutic potential of Tsg101 to prevent/reduce I/R-induced cardiac energy stress and injury, using Tsg101-loaded exosomes. The proposed studies are expected to identify Tsg101 as a novel regulator of Glut-4 translocation and as a major cardio-protector against I/R-induced energy stress. If verified, the findings from this proposal should provide new and safe strategies to increase energy generation in I/R hearts and hopefully, minimize surgically induced cardiac I/R injury.

冠状动脉搭桥术 (CABG) 和移植的心脏手术通常涉及心脏 缺血/再灌注 (I/R)，导致心肌能量来源从脂肪酸 β- 转变 作为一种适应，Glut-4 是葡萄糖转运蛋白的主要亚型。 心脏，被招募到心肌细胞表面（也称为肌膜）以吸收葡萄糖并刺激 然而，这种代偿性 Glut4 易位不足以满足心脏 ATP 的产生。 I/R 心脏中 ATP 生成需要葡萄糖，从而导致能源危机。 多项涉及向患者输注葡萄糖-胰岛素-钾 (GIK) 溶液的大型临床试验 接受心脏手术并没有显示出任何积极的结果（甚至更糟），因此正在探索如何进行。 迫切需要独立于胰岛素来增强 Glut-4 易位和葡萄糖利用 我们最近做出了新的发现，即肿瘤易感性。 基因 101 (Tsg101)，ESCRT（运输所需的内体分选复合物）的核心组成部分 机械，能够调节动物心脏膜受体的内体回收。 数据进一步表明：1) Tsg101 直接与成年小鼠心脏中的 Glut-4 结合；2) 强制表达 当培养的心肌细胞中的 Tsg101 导致肌膜 Glut-4 水平升高并提高细胞存活率时， 受到缺氧/复氧的挑战；3) Tsg101 上调 Rab11a 和 FIP3 的表达 （Rab11 家族相互作用蛋白 3），参与内体回收的两个关键因素最重要的是，我们的。 试点数据还表明，一组天然存在的纳米囊泡，即外泌体，由骨释放 骨髓干细胞可以有效地将 Tsg101 传递到心肌细胞中，基于这些初步发现，我们。 证实 Tsg101 可以通过促进 Rab11a/ 来减少或预防心脏缺血再灌注引起的能量危机/损伤 FIP3 介导的 Glut-4 内体回收利用含有 Tsg101 的外泌体治疗小鼠心脏。 缺血前或早期再灌注期间可升高心肌 Tsg101，从而限制 I/R 触发的 这里提出的工作将解决三个具体目标：1) 定义 Tsg101 在心脏损伤中的作用。 葡萄糖依赖性能量产生和心脏保护免受 I/R 损伤，使用心脏特异性 2) 鉴定是否由Tsg101诱导 心脏保护依赖于 Rab11a/FIP3 介导的 Glut-4 和 3) 内体再循环； 研究 Tsg101 预防/减少缺血再灌注引起的心脏能量应激的治疗潜力 和损伤，使用 Tsg101 负载的外泌体拟议的研究预计将确定 Tsg101 作为一个。 Glut-4 易位的新型调节剂，作为对抗 I/R 引起的能量应激的主要心脏保护剂。 经过验证，该提案的研究结果应提供新的、安全的策略来增加能源发电 在 I/R 心脏中，希望能最大限度地减少手术引起的心脏 I/R 损伤。

项目成果

Identification of a Novel Antisepsis Pathway: Sectm1a Enhances Macrophage Phagocytosis of Bacteria through Activating GITR.

新型抗菌途径的鉴定：Sectm1a 通过激活 GITR 增强巨噬细胞对细菌的吞噬作用。

• DOI: 10.4049/jimmunol.2000440
• 发表时间: 2020
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Mu,Xingjiang;Wang,Peng;Wang,Xiaohong;Li,Yutian;Zhao,Hongyan;Li,Qianqian;Essandoh,Kobina;Deng,Shan;Peng,Tianqing;Fan,Guo-Chang
• 通讯作者: Fan,Guo-Chang

Administration of nicotinamide riboside prevents oxidative stress and organ injury in sepsis.

• DOI: 10.1016/j.freeradbiomed.2018.05.073
• 发表时间: 2018-08-01
• 期刊: Free radical biology & medicine
• 影响因子: 7.4
• 作者: Hong G;Zheng D;Zhang L;Ni R;Wang G;Fan GC;Lu Z;Peng T
• 通讯作者: Peng T

Macrophage Efferocytosis in Cardiac Pathophysiology and Repair.

• DOI: 10.1097/shk.0000000000001625
• 发表时间: 2021-02-01
• 期刊: Shock (Augusta, Ga.)
• 作者: Li Y;Li Q;Fan GC
• 通讯作者: Fan GC

Nicotinamide riboside promotes autolysosome clearance in preventing doxorubicin-induced cardiotoxicity.

• DOI: 10.1042/cs20181022
• 发表时间: 2019-07
• 期刊: Clinical science
• 影响因子: 6
• 作者: D. Zheng;Yi Zhang;Ming Zheng;T. Cao;Grace Wang;Lulu Zhang;R. Ni;J. Brockman;Huiting Zhong;G. Fan;T. Peng

An Hsp20-FBXO4 Axis Regulates Adipocyte Function through Modulating PPARγ Ubiquitination.

• DOI: 10.1016/j.celrep.2018.05.065
• 发表时间: 2018-06-19
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Peng J;Li Y;Wang X;Deng S;Holland J;Yates E;Chen J;Gu H;Essandoh K;Mu X;Wang B;McNamara RK;Peng T;Jegga AG;Liu T;Nakamura T;Huang K;Perez-Tilve D;Fan GC
• 通讯作者: Fan GC