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.

冠状动脉旁路移植术（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- 氧化为厌氧糖酵解。作为一种适应，Glut-4，一种主要的同种型的葡萄糖转运蛋白， 心脏，被招募到心肌细胞表面（也称为肌膜），以摄取葡萄糖并刺激 心脏ATP生成。尽管如此，这种代偿性Glut 4易位不足以满足心脏 I/R心脏中ATP生成需要葡萄糖，从而导致能量危机。值得注意的是， 涉及向患者输注葡萄糖-胰岛素-钾（GIK）溶液的多项大型临床试验 接受心脏手术的患者没有任何积极的结果（甚至更糟）。因此，探索如何 增加Glut-4易位和葡萄糖利用，独立于胰岛素， 对抗I/R触发的心脏能量损失我们最近有了新的发现， 基因101（Tsg 101），ESCRT（转运所需的内体分选复合物）的核心组分 机械，能够调节动物心脏中膜受体的内体再循环。我们最新 数据进一步显示：1）Tsg 101在成年小鼠心脏中直接结合Glut-4; 2）Tsg 101的强制表达， 在培养的心肌细胞中，Tsg 101导致更高水平的肌膜Glut-4，并改善细胞存活， Tsg 101上调Rab 11 a和FIP 3的表达 （Rab 11家族相互作用蛋白3），参与内体再循环的两个关键因子。最重要的是我们的 试验数据还表明，一组天然存在的纳米囊泡，外泌体，由骨释放， 骨髓干细胞可以有效地将Tsg 101递送到心肌细胞中。基于这些初步发现，我们 假设Tsg 101可以通过促进Rab 11 a/ FIP 3介导的Glut-4的内体再循环。用含有Tsg 101的外泌体处理小鼠心脏 缺血前或再灌注早期心肌Tsg 101升高，从而限制I/R触发的 心脏损伤这里提出的工作将解决三个具体目标：1）定义Tsg 101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 Tsg 101过表达和诱导型敲低小鼠模型; 2）鉴定Tsg 101是否诱导 心脏保护依赖于Rab 11 a/FIP 3介导的Glut-4的内体再循环;和3） 研究Tsg 101预防/减少I/R诱导的心脏能量应激的治疗潜力 和损伤。拟议的研究预计将确定Tsg 101为 Glut-4易位的新调节剂，并作为对抗I/R诱导的能量应激的主要心脏保护剂。如果 经过验证，该提案的研究结果应该为增加能源生产提供新的安全战略 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

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

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