Exercise-Induced Shear Stress Modulates Metabolic Pathways for Vascular Repair and Protection

运动引起的剪切应力调节血管修复和保护的代谢途径

• 批准号: 10436918
• 负责人: Tzung K Hsiai
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436918
• 关键词: 3-Dimensional; 6-Phosphofructo-2-kinase; Afghanistan; Agonist; Arterial Fatty Streak; Atherosclerosis; Attenuated; Autophagosome; Biological Markers; Biology; Blood Vessels; Caliber; Cardiovascular Diseases; DNA Damage; Detection; Development; Dominant-Negative Mutation; Electrodes; Endothelium; Exercise; Fatty Acids; Frequencies; Fructose; Genetic Models; Glycolysis; Gulf War; Health; Homeostasis; Hyperlipidemia; Impairment; Lesion; Life Style Modification; Lipids; MAPK8 gene; Mechanics; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic syndrome; Middle East; Mitochondria; Mitochondrial DNA; Modeling; Mus; N-terminal; NADPH Oxidase; Natural regeneration; Nature; New Zealand; Nuclear Hormone Receptors; Oryctolagus cuniculus; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Phase; Phosphotransferases; Production; Pulsatile Flow; Receptor Signaling; Risk Factors; Signal Pathway; Signal Transduction; Spectrum Analysis; Stress; Testing; Therapeutic; Tissues; Vascular Endothelial Cell; Vascular regeneration; Veterans; Wild Type Mouse; dielectric property; electric impedance; electrical property; exercise intervention; flexibility; heart disease risk; hemodynamics; insight; lipid metabolism; metabolomics; monocyte; oxidized low density lipoprotein; protein aggregation; recruit; repaired; response; rosiglitazone; sensor; shear stress; therapeutic target

Exercise-Induced Shear Stress Modulates Metabolic Pathways for Vascular Repair and Protection Cardiovascular and metabolic diseases are on the rise in our veterans returning from battlefields in Afghanistan and the Middle East, and exercise intervention remains an effective lifestyle modification. Hemodynamic stress forces modulate both metabolic and mechanical effects on vascular endothelial cells, mediating the focal and eccentric nature of atherosclerotic lesions. The advent in metabolomics and metabolic profiling has led to the discovery of new metabolic biomarkers and therapeutic targets. We established that bidirectional oscillatory flow impairs autophagic flux, perturbing mitochondrial homeostasis. In contrast, unidirectional pulsatile flow attenuated mitochondrial DNA damage to maintain endothelial homeostasis. In parallel, we developed flexible micro-electrochemical impedance sensors for detection of metabolically active atherosclerotic lesions in the New Zealand White (NZW) rabbit model. We demonstrated that oxidized Low- Density Lipoprotein (oxLDL) in atherosclerotic lesions display distinct frequency-dependent electrical and dielectrical properties. Our preliminary studies revealed that pulsatile and oscillatory flow differentially modulated metabolic pathways to promote vascular regeneration and athero-protection. We demonstrated that flow-sensitive arterial metabolic changes were detected by electrochemical impedance spectroscopy (EIS). Furthermore, our metabolomics analyses revealed that PSS vs. OSS differentially activates PKCɛ-6- phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) signaling to increase glycolytic metabolites, but to decrease gluconeogenic metabolites, for vascular repair and regeneration. Metabolomics analyses further uncovered flow-sensitive nuclear hormone receptor peroxisome proliferator-activated receptor  (PPAR)-dependent fatty acid metabolites to mitigate monocyte recruitment. In this context, we hypothesize that exercise-augmented pulsatile shear stress (PSS) modulates glycolytic and lipid metabolic pathways to influence vascular regeneration and protection, leading to the arterial metabolic changes that can be detected by 3-D EIS mapping. To test our hypothesis, we have three aims. In Aim 1, we will determine if flow-mediated PKCε signaling modulates glycolytic metabolites for vascular regeneration. We hypothesize that PSS and OSS differentially modulate PKCε-PFKFB3 signaling pathway to regulate production of glycolytic metabolites. In Aim 2, we will determine if flow-sensitive PPAR signaling modulates lipid metabolites for vascular protection. We hypothesize that PSS and OSS differentially modulate PPAR-SCD-1 signaling to regulate production of fatty acid metabolites. In Aim 3, we will demonstrate shear stress-PPAR- mediated arterial metabolic changes by 3-D EIS mapping. We hypothesize that PPAR-SCD1-mediated metabolic changes can be interrogated by 3-D EIS mapping. Overall, the integration of vascular biology, hemodynamic forces and metabolomic profiling will provide metabolic insights into flow modulation of glycolytic and lipid metabolisms to discover new biomarkers with therapeutic implications for our veterans at risk for heart disease and metabolic syndromes.

运动引起的剪切应力调节血管修复和保护的代谢途径 从战场归来的退伍军人中，心血管和代谢疾病呈上升趋势 在阿富汗和中东地区，运动干预仍然是一种有效的生活方式改变方式。 血流动力学应力调节血管内皮细胞的代谢和机械效应， 介导动脉粥样硬化病变的局灶性和偏心性代谢组学和代谢的出现。 分析导致了新的代谢生物标志物和治疗靶点的发现。 双向振荡流会损害自噬通量，扰乱线粒体稳态。 单向脉动流减轻线粒体 DNA 损伤，维持内皮稳态。 与此同时，我们开发了灵活的微电化学阻抗传感器，用于检测代谢活性 我们在新西兰白兔（NZW）模型中证明了动脉粥样硬化病变。 动脉粥样硬化病变中的密度脂蛋白（oxLDL）表现出明显的频率依赖性电和 我们的初步研究表明，脉动流和振荡流存在差异。 调节代谢途径以促进血管再生和动脉粥样硬化保护。 通过电化学阻抗谱（EIS）检测血流敏感的动脉代谢变化。 此外，我们的代谢组学分析表明，PSS 与 OSS 不同地激活 PKCɛ-6- 磷酸果糖-2-激酶/果糖-2,6-二磷酸酶 3 (PFKFB3) 信号传导可增加糖酵解代谢物， 但减少糖异生代谢物，用于血管修复和再生分析。 进一步发现了流敏感核激素受体过氧化物酶体增殖物激活受体 - (PPAR-) 依赖性脂肪酸代谢物可减轻单核细胞募集在这种情况下，我们勇敢地面对。 运动增强的脉动剪切应力 (PSS) 调节糖酵解和脂质代谢 影响血管再生和保护的途径，导致动脉代谢变化 为了检验我们的假设，我们在目标 1 中设定了三个目标。 确定血流介导的 PKCε 信号传导是否调节糖酵解代谢物以促进血管再生。 认为 PSS 和 OSS 差异调节 PKCε-PFKFB3 信号通路来调节生产 在目标 2 中，我们将确定流量敏感的 PPAR 信号传导是否调节脂质。 我们勇敢地说 PSS 和 OSS 差异调节 PPAR-SCD-1。 在目标 3 中，我们将展示剪切应力-PPAR-。 通过 3-D EIS 映射介导动脉代谢变化，我们勇敢地承认 PPAR-SCD1 介导。 代谢变化可以通过 3-D EIS 绘图来询问 总体而言，血管生物学的整合， 血流动力学和代谢组学分析将为糖酵解的流量调节提供代谢见解 和脂质代谢，以发现对有心脏病风险的退伍军人具有治疗意义的新生物标志物 疾病和代谢综合征。