Repair of Vascular Contractility and Mitochondrial Function by NOS Recoupling

NOS 重新偶联修复血管收缩力和线粒体功能

• 批准号: 10266011
• 负责人: Amy Celeste Keller
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266011
• 关键词: Acetylcholine; Address; Affect; Animal Model; Antioxidants; Applications Grants; Attenuated; Biochemical; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cells; Citric Acid Cycle; Communities; Coupling; Cyclic GMP; Data; Defect; Development; Diabetes Mellitus; Dietary Factors; Disease; End Point Assay; Endothelial Cells; Endothelium; Environment; Enzymes; Etiology; Event; Exposure to; Flavonoids; Food; Functional disorder; Generations; Glucose; Glycolysis; Goals; Health; Homeostasis; Human; Impairment; In Vitro; Incubated; Intervention; Investigation; Lead; Link; Lipids; Location; Measures; Metabolic; Metabolism; Mitochondria; Modification; NADPH Oxidase; NG-Nitroarginine Methyl Ester; Natural Products; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nutrient; Oxidation-Reduction; Pathologic; Pathology; Pharmacologic Substance; Physiological; Placebos; Plants; Potassium; Process; Production; Rattus; Reactive Oxygen Species; Regulation; Research; Respiration; Risk Factors; Role; Signal Pathway; Signal Transduction; Source; Stress; Supplementation; Testing; Therapeutic; Therapeutic Uses; Time; Tissues; Vasodilation; Venous; Veterans; Work; Xanthine Oxidase; cardiovascular disorder risk; cell growth regulation; dimer; epicatechin; experimental study; glucose metabolism; improved; in vivo; lipid metabolism; metabolomics; military veteran; mitochondrial dysfunction; monomer; new therapeutic target; novel; oxidation; protein expression; repair enzyme; repaired; resilience; response; restoration; sensor; vascular abnormality; vascular endothelial dysfunction

Diabetes (DM) is prevalent in the Veteran community, and there is an excess risk of cardiovascular disease (CVD) in those suffering from this disease. Early signs of CVD pathology include disruptions in vascular cells, making the vasculature a prime target for novel therapeutics. Hormesis, or the ability of cells to adapt and self- regulate when exposed to stress, is disrupted in the vasculature of those with DM. A central lynchpin of homeostasis modulation is the enzyme nitric oxide synthase (NOS). NOS regulates vascular contractility through the production of nitric oxide (NO) and also modulates mitochondrial function. We have shown that the impaired vascular function in animal models of DM is correlated to NOS dysfunction and altered mitochondrial substrate metabolism, function, and dynamics. It is unknown whether restoration of mitochondrial substrate metabolism would repair NOS activity, cellular and mitochondrial function, redox processes, and/or vascular function in those with DM. We hypothesize that disrupted cellular homeostasis intrinsic to the DM vasculature can be restored by reestablishing physiological NOS regulation and mitochondrial fuel metabolism. Many bioactive plant compounds are a platform for commonly used pharmaceuticals and have myriad physiological effects. The flavonoid compound -(-) epicatechin has been shown to induce vasodilation through the direct modulation of NOS; in previous studies, this compound also attenuated excess ROS and improved mitochondrial function. To test our hypothesis, we will treat animal models of DM with the plant compound -(-) epicatechin and measure NOS activity, mitochondrial function and substrate utilization, and vascular contractility. In vitro experiments in endothelial cells treated with -(-) epicatechin will determine the upstream cellular regulation of our functional endpoints. Secondly, we will test the cellular regulation of antioxidant defense in endothelial cells treated with -(-) epicatechin and ascertain any effects on cellular signaling pathways. Ultimately, we will investigate whether the cells' innate homeostatic regulation will be restored by repairing NOS activity with this plant compound. As this natural product is available in food and as a supplement, it may be a candidate for immediate therapeutic use for Veterans suffering from DM and CVD.

糖尿病（DM）在退伍军人社区中普遍存在，并且心血管疾病的风险过高 (CVD)在那些患有这种疾病的人身上。CVD病理学的早期迹象包括血管细胞的破坏， 使脉管系统成为新疗法的主要目标。激效效应，或者说细胞适应和自我调节的能力， 在糖尿病患者的血管系统中，当暴露于压力时，调节被破坏。一个中心的关键 体内平衡调节是一氧化氮合酶（NOS）。NOS调节血管收缩性 通过一氧化氮（NO）的产生，并且还调节线粒体功能。我们已经证明 糖尿病动物模型血管功能受损与NOS功能障碍有关， 线粒体底物代谢、功能和动力学。目前尚不清楚是否恢复 线粒体底物代谢可修复NOS活性、细胞和线粒体功能、氧化还原 过程和/或血管功能。我们假设破坏了细胞内稳态 DM血管系统固有的可以通过重建生理NOS调节来恢复， 线粒体燃料代谢许多具有生物活性的植物化合物是一个平台， 药物，并具有无数的生理效应。类黄酮化合物-（-）表儿茶素已被 显示通过直接调节NOS诱导血管舒张;在先前的研究中，该化合物还 减少过量的ROS并改善线粒体功能。为了验证我们的假设，我们将动物 用植物化合物-（-）表儿茶素复制DM模型，并测定NOS活性、线粒体功能和 底物利用和血管收缩性。- （-）处理的内皮细胞的体外实验 表儿茶素将决定我们的功能终点的上游细胞调节。其次，我们将测试 用-（-）表儿茶素处理的内皮细胞中抗氧化防御的细胞调节，并确定任何 对细胞信号通路的影响。最终，我们将研究细胞的先天自我平衡 调节将通过用该植物化合物修复NOS活性而恢复。由于这种天然产物是 作为一种食物和补充剂，它可能是退伍军人立即治疗的候选者。 患有DM和CVD。