Effect of CTHRC1 on endothelial cell survival after acute ischemia

CTHRC1对急性缺血后内皮细胞存活的影响

• 批准号: 10531574
• 负责人: VOLKHARD LINDNER
• 金额: $ 53.46万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-20 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10531574
• 关键词: Acute; Address; Adult; Apoptosis; Apoptotic; Blood; Body Composition; Brain; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cell Survival; Cells; Cellular Assay; Cellular Metabolic Process; Cellular Stress; Circulation; Collagen; Coronary artery; Data; Development; Endothelial Cells; Energy Metabolism; Environment; Event; Fibroblasts; Foundations; Genetic; Glucose; Glycolysis; Goals; Heart; Heart Arrest; Hormones; Hour; Human; In Vitro; Individual; Inflammation; Ischemia; Knockout Mice; Laboratories; Ligation; Mediator; Metabolic; Metabolism; Minority; Mitochondria; Modeling; Molecular; Monitor; Mouse Strains; Mus; Myocardial Infarction; Myocardial Ischemia; Outcome; Oxygen; Pathway interactions; Patients; Pattern; Perfusion; Pericytes; Phase; Phenotype; Physical activity; Physiological; Plasma; Production; Publishing; Rattus; Regulatory Pathway; Respiration; Rest; Role; Sampling; Signal Transduction; Site; Source; Stress; Survival Rate; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Up-Regulation; Wild Type Mouse; angiogenesis; bone; cardiovascular health; cell type; coronary artery occlusion; energy efficiency; experience; human subject; improved outcome; in vivo; injured; injury and repair; interstitial cell; ischemic injury; mortality; mouse model; novel; novel therapeutic intervention; overexpression; predictive modeling; promoter; protective effect; repaired; respiratory; response; source localization; tissue injury; triple helix

Abstract In previous studies we have demonstrated that CTHRC1 (Collagen Triple Helix Repeat Containing 1), a factor discovered in our laboratory, is constitutively expressed only in brain and bone and not in other tissues during adulthood. However, CTHRC1 is highly expressed in activated fibroblasts and interstitial cells of tissues undergoing remodeling and repair. We discovered that CTHRC1 is a circulating factor but only approximately 30% of healthy human subjects have detectable levels of CTHRC1 in plasma, ranging in concentration from low pg/ml to almost 100ng/ml. Similar to most humans, circulating levels of CTHRC1 are not detectable in mice and rats and forced transgenic overexpression of CTHRC1 under Pdgfrb promoter control does also not result in detectable CTHRC1 plasma levels. Thus there are two pools of CTHRC1; one that is generated locally in tissues undergoing repair requiring >48 hours to be available, and a second pool of circulating CTHRC1 available at all times and found only in a minority of human subjects. The significance of circulating CTHRC1 for the cardiovascular system became apparent when we obtained plasma samples from patients experiencing cardiac arrest, a condition with approximately 50% mortality. High CTHRC1 levels (≥0.75ng/ml) are associated with substantially higher survival rates in humans experiencing cardiac arrest. While CTHRC1 is not expressed in the adult heart, it is highly induced in fibroblasts activated in response to myocardial infarction. To test the role of CTHRC1 in acute ischemic injury, we performed coronary artery ligation in Cthrc1 null mice and Cthrc1 transgenic mice on the Cthrc1 null background with physiologically relevant CTHRC1 plasma levels in the ng/ml range found in humans. Strikingly, 70% of Cthrc1 null mice died 3-4 days after the ischemic injury whereas all transgenic mice survived. With the goal of identifying the mechanism for this dramatic finding we performed in vitro studies and found that CTHRC1 promotes cell survival in variety of cell types including endothelial cells. Complete metabolic monitoring revealed that Cthrc1 null mice have increased energy expenditure at rest and analysis of cell metabolism in vitro revealed that in the presence of CTHRC1 mitochondrial respiration is significantly increased whereas glycolysis is reduced, leading us to hypothesize that CTHRC1 functions as a mediator of metabolic efficiency. Overall, this proposal will test the hypothesis that CTHRC1 functions as a mediator of cell survival under conditions of cell stress by increasing metabolic efficiency, which in turn protects from the deadly consequences of acute ischemic injury. We will determine if increasing circulating- or CTHRC1 tissue levels provides cardiovascular protection by limiting the deleterious consequences of myocardial ischemia. Using genetic mouse models and in vitro approaches the underlying mechanism of action will be identified, and this will provide the foundation for novel therapeutic approaches to improve outcomes of acute ischemic conditions.

抽象的 在之前的研究中，我们已经证明 CTHRC1（含有 1 的胶原蛋白三螺旋重复序列）是一个因子 我们实验室发现的，仅在大脑和骨骼中组成型表达，在其他组织中不表达 然而，在成年期，CTHRC1 在激活的成纤维细胞和组织间质细胞中高度表达。 我们发现 CTHRC1 是一个循环因子，但只是近似的。 30% 的健康人类受试者血浆中可检测到 CTHRC1 水平，浓度范围为 与大多数人类相似，CTHRC1 的循环水平在小鼠体内检测不到。 大鼠和 Pdgfrb 启动子控制下的 CTHRC1 强制转基因过度表达也不会导致 在可检测的 CTHRC1 血浆水平中，存在两种 CTHRC1 池；一种是在体内本地产生的。 需要 >48 小时才能使用的正在进行修复的组织，以及第二个循环 CTHRC1 池 任何时候都存在且仅在少数人类受试者中发现循环 CTHRC1 的重要性。 当我们从患有以下疾病的患者身上获取血浆样本时，心血管系统的影响就变得明显了 心脏骤停，这种情况与高 CTHRC1 水平（≥0.75ng/ml）相关。 在发生心脏骤停的人类中，存活率显着提高，而 CTHRC1 不表达。 在成人心脏中，它在响应心肌梗塞而激活的成纤维细胞中被高度诱导。 CTHRC1 在急性缺血性损伤中的作用，我们对 Cthrc1 缺失小鼠和 Cthrc1 进行冠状动脉结扎 CTHRC1 零背景上的转基因小鼠，其生理相关的 CTHRC1 血浆水平 令人惊讶的是，70% 的 Cthrc1 缺失小鼠在缺血性损伤后 3-4 天死亡。 而所有转基因小鼠都存活了下来，为了确定这一戏剧性发现的机制，我们 进行体外研究，发现 CTHRC1 促进多种细胞类型的细胞存活，包括 完整的代谢监测显示 Cthrc1 缺失小鼠的能量增加。 静息消耗和体外细胞代谢分析表明，在 CTHRC1 存在的情况下 线粒体呼吸显着增加，而糖酵解减少，导致我们陷入困境 总体而言，该提案将检验以下假设：CTHRC1 作为代谢效率的调节因子。 CTHRC1 通过增加代谢在细胞应激条件下充当细胞生存的介质 效率，进而防止急性缺血性损伤的致命后果。 增加循环或 CTHRC1 组织水平可通过限制有害物质来提供心血管保护。 使用遗传小鼠模型和体外方法研究心肌缺血的后果。 将确定作用机制，这将为新的治疗方法奠定基础 改善急性缺血性疾病的结果。

项目成果

Activated CTHRC1 promotes glycolysis in endothelial cells: Implications for metabolism and angiogenesis.

激活的 CTHRC1 促进内皮细胞糖酵解：对代谢和血管生成的影响。

• 发表时间: 2023-12
• 影响因子: 4
• 作者: Toomey, Barbara H;Mitrovic, Sarah A;Lindner;Leon Vazquez, Ruth G;Kacer, Doreen;Ryzhov, Sergey;Prudovsky, Igor;Lindner, Volkhard
• 通讯作者: Lindner, Volkhard

Tgfβ1-Cthrc1 Signaling Plays an Important Role in the Short-Term Reparative Response to Heart Valve Endothelial Injury.

Tgfβ1-Cthrc1 信号传导在心脏瓣膜内皮损伤的短期修复反应中发挥重要作用。

• 发表时间: 2021-12
• 作者: Nordquist, Emily M;Dutta, Punashi;Kodigepalli, Karthik M;Mattern, Carol;McDermott, Michael R;Trask, Aaron J;LaHaye, Stephanie;Lindner, Volkhard;Lincoln, Joy
• 通讯作者: Lincoln, Joy

Single-Cell RNA Sequencing Analysis Reveals a Crucial Role for CTHRC1 (Collagen Triple Helix Repeat Containing 1) Cardiac Fibroblasts After Myocardial Infarction.

单细胞 RNA 测序分析揭示了 CTHRC1（含有 1 的胶原三螺旋重复序列）心脏成纤维细胞在心肌梗死后的重要作用。

• 发表时间: 2020
• 影响因子: 37.8
• 作者: Ruiz;Romero, Juan P;Hernández, Silvia C;Vilas;Fortelny, Nikolaus;Castro;San Martin;Lorenzo;García;Palacio, Marcel;Gavira, Juan José;Bastarrika, Gorka;Janss
• 通讯作者: Janss