Repair of Vascular Contractility and Mitochondrial Function by NOS Recoupling

糖尿病(DM)在退伍军人社区中很普遍，而且患心血管疾病的风险过高 (CVD)对患有这种疾病的人。脑血管病变的早期迹象包括血管细胞的破坏， 使血管系统成为新疗法的主要目标。兴奋作用，或细胞适应和自我调节的能力 当暴露在压力下时，糖尿病患者血管系统中的调节被破坏。一个核心的关键 动态平衡调节是一氧化氮合酶(NOS)。一氧化氮合酶对血管收缩的调节作用 通过产生一氧化氮(NO)，也调节线粒体的功能。我们已经证明了 糖尿病动物模型血管功能受损与一氧化氮合酶功能紊乱及改变的关系 线粒体底物代谢、功能和动力学。目前尚不清楚是否会修复 线粒体底物代谢会修复一氧化氮合酶活性、细胞和线粒体功能、氧化还原 糖尿病患者的病变过程和/或血管功能。我们假设破坏了细胞内环境的平衡 DM血管系统的固有功能可以通过重建生理性的NOS调节和 线粒体燃料代谢。许多具有生物活性的植物化合物都是常用的 药物，有无数的生理作用。黄酮类化合物-(-)表儿茶素 通过一氧化氮合酶的直接调节来诱导血管扩张；在以前的研究中，这种化合物还 减轻过量的ROS，改善线粒体功能。为了验证我们的假设，我们将用动物 用植物化合物-(-)表儿茶素建立糖尿病模型，并测定一氧化氮合酶活性、线粒体功能和 底物利用率和血管收缩能力。-(-)处理内皮细胞的体外实验 表儿茶素将决定我们功能终点的上游细胞调节。第二，我们将测试 -(-)表儿茶素对内皮细胞抗氧化防御的调节作用 对细胞信号通路的影响。最终，我们将调查这些细胞的先天动态平衡 用这种植物化合物修复一氧化氮合酶活性将恢复调节。因为这种天然产品是 可用于食品和作为补充剂，它可能是退伍军人立即治疗的候选药物 患有糖尿病和心血管疾病。

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.