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.

切应力调控血管修复和保护的代谢途径 年，从战场返回的退伍军人中，心血管和代谢疾病的发病率正在上升。 阿富汗和中东，运动干预仍然是一种有效的生活方式改变。 血流动力学应力调节对血管内皮细胞的代谢和机械作用， 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 谱分析导致了新的代谢生物标志物和治疗靶点的发现。我们确定， 双向振荡流动损害自噬通量，扰乱线粒体动态平衡。与此相反的是， 单向脉动流减弱线粒体DNA损伤以维持内皮稳态。在 平行，我们开发了灵活的微电化学阻抗传感器检测代谢活性 新西兰白色（NZW）兔模型中的动脉粥样硬化病变。我们证明了氧化的低- 动脉粥样硬化病变中的密度脂蛋白（oxLDL）显示出明显的频率依赖性电活动， 介电性能我们的初步研究表明，脉动流和振荡流的差异， 调节代谢途径以促进血管再生和动脉粥样硬化保护。我们证明了 通过电化学阻抗谱（EIS）检测流量敏感性动脉代谢变化。 此外，我们的代谢组学分析显示，PSS与OSS差异激活PKC β-6- 磷酸果糖-2-激酶/果糖-2，6-二磷酸酶3（PFKFB 3）信号传导以增加糖酵解代谢物， 还能减少血管生成代谢物，促进血管修复和再生。代谢组学分析 进一步揭示了流动敏感性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以减轻单核细胞募集。在这种情况下，我们假设 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 这可以通过三维EIS映射来检测。为了验证我们的假设，我们有三个目标。在目标1中，我们 确定血流介导的PKCε信号是否调节血管再生的糖酵解代谢物。我们 推测PSS和OSS通过不同方式调节PKCε-PFKFB 3信号通路来调节蛋白质合成 糖酵解代谢物的合成在目标2中，我们将确定是否流动敏感的PPAR-beta信号调节脂质 代谢物用于血管保护。我们假设PSS和OSS对PPAR-SCD-1的调节是不同的， 信号传导以调节脂肪酸代谢物的产生。在目标3中，我们将证明剪切应力-PPAR γ- 介导的动脉代谢变化的三维EIS映射。我们推测，PPAR-SCD 1介导的 可以通过3-D EIS绘图来询问代谢变化。总的来说，血管生物学的整合， 血液动力学力和代谢组学分析将提供对糖酵解的流动调节的代谢见解。 和脂质代谢，以发现新的生物标志物，对我们有心脏病风险的退伍军人具有治疗意义。 疾病和代谢综合征。