Role of Cytoglobin in the Regulation of Vascular Tone

细胞红蛋白在血管张力调节中的作用

• 批准号: 10586975
• 负责人: JAY Louis ZWEIER
• 金额: $ 77.79万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586975
• 关键词: Accounting; Affect; Angiotensins; Antioxidants; Biological Assay; Biological Availability; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Computer Models; Cytochromes b5; Data; Development; Diffusion; Dioxygenases; Disease; Endothelium; Evaluation; Globin; Grant; Hemeproteins; Heterozygote; Histology; Hypertension; Knockout Mice; Knowledge; Measurement; Measures; Mediating; Mediator; Metabolism; Mus; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Oxidation-Reduction; Oxidoreductase; Peroxonitrite; Physiological; Physiology; Process; Property; Publishing; Reaction; Regulation; Relaxation; Reporting; Research; Resistance; Role; Smooth Muscle; Soluble Guanylate Cyclase; Spin Trapping; Superoxide Dismutase; Superoxides; Support System; Systemic blood pressure; Testing; Thick; Vascular Diseases; Vascular Smooth Muscle; heart function; hypertensive; in vivo; in vivo evaluation; inhibitor; insight; mathematical model; mimetics; mouse model; novel; novel therapeutic intervention; novel therapeutics; overexpression; preservation; programs; response

Endothelium-derived nitric oxide (NO), is a key mediator regulating vascular tone and blood pressure. NO mediates vascular relaxation through activation of soluble guanylate cyclase (sGC) in the smooth muscle. While NO is synthesized by NO synthase in the endothelium, the process of vascular NO degradation and metabolism in smooth muscle is poorly understood. NO degradation in the vessel wall is mediated by an O2- dependent NO dioxygenase (NOD) that oxidizes NO to nitrate. Cytoglobin (Cgb) is a recently discovered globin expressed in smooth muscle (but not in the endothelium) with previously unknown function. Cgb is proposed to serve as a critical regulator of the rate of O2-dependent NO metabolism in the vessel wall, in turn regulating vascular tone. Over the prior grant period: 1) we demonstrated that Cgb is the major heme protein that regulates the rate of O2-dependent NO metabolism in the smooth muscle of both conduit and resistance vessels and, in turn, profoundly modulates vascular tone; 2) we identified that cytochrome b5 (B5)/ B5 reductase (B5R) constitutes the major Cgb reducing system that supports this NOD function; 3) we discovered that Cgb has potent superoxide dismutase (SOD) function accounting for its previously unexplained antioxidant effects; 4) most recently, we identified novel selective inhibitors of Cgb NOD function that do not impair its SOD function and were shown in vessels to enhance NO mediated sGC activation. However, major questions remain regarding the overall process of NO decay in the vessel wall, how this varies in disease, and how it can be modulated to ameliorate disease. In the next stage of this grant program, we seek to determine how the NO degrading and SOD/antioxidant properties of Cgb in the vessel wall control the processes of NO and redox metabolism in normal and hypertensive vessels, and how this in turn regulates vessel tone and systemic blood pressure. The critical effects of Cgb expression levels and the modulation of its NOD activity will be determined. Studies will be performed first in isolated vessels and then in the in vivo cardiovascular system, with measurements in our genetically modified mouse lines with Cgb-/-, Cgb-/+ and Cgb overexpression as well as compounds that selectively inhibit Cgb NOD function. Studies will also be performed in our recently developed conditional smooth muscle-selective Cgb-/- mouse to definitively characterize the role of Cgb in smooth muscle. Studies will focus on the physiological regulation that occurs in normal non-hypertensive mice and then on angiotensin-induced hypertension. All the data obtained will be used to support computational modeling that will enable us to predict the effects of modulating Cgb expression and its NO metabolizing function. Accomplishment of this research plan will elucidate how Cgb levels and its NOD and SOD function regulates O2-dependent NO metabolism and the redox state of the vessel, thus providing important insights into the regulation of vascular tone in normal physiology and cardiovascular disease. This knowledge will lead to new therapeutic approaches to treat or reverse hypertension and other cardiovascular disease.

内皮衍生的一氧化氮（NO）是调节血管张力和血压的关键介体。不 通过在平滑肌中激活可溶性鸟苷酸环化酶（SGC），介导血管松弛。 虽然在内皮中没有合成酶合成不合成，但血管的过程无降解和 平滑肌中的代谢知之甚少。容器壁中没有降解是由O2-介导的 依赖性NO氧化为硝酸盐的二加氧酶（点头）。细胞神经蛋白（CGB）是最近发现的环球蛋白 以平滑肌（但不在内皮中）表达，具有以前未知的功能。提议CGB 作为依赖O2依赖性无代谢速率的关键调节剂，反过来调节 血管音。在以前的赠款期间：1）我们证明了CGB是主要的血红素蛋白 调节导管和电阻平滑肌中O2依赖性无代谢的速率 船只，反过来深刻调节血管张力； 2）我们确定了细胞色素B5（B5）/ B5 还原酶（B5R）构成了支持此NOD功能的主要CGB还原系统。 3）我们发现了 该CGB具有有效的超氧化物歧化酶（SOD）功能，该功能涉及其先前无法解释的抗氧化剂 效果； 4）最近，我们确定了不损害其SOD的CGB NOD功能的新型选择性抑制剂 功能并在血管中显示，以增强未介导的SGC激活。但是，主要问题 关于血管壁中无衰减的整体过程，这种疾病的变化以及如何变化 适应改善疾病。在此赠款计划的下一阶段，我们试图确定否 CGB在容器壁中的降解和SOD/抗氧化特性控制NO和氧化还原的过程 正常和高血压血管中的代谢，以及这如何调节血管的音调和全身血液 压力。 CGB表达水平及其NOD活性的调节的关键作用将是 决定。研究将首先在孤立的血管中进行，然后在体内心血管系统中进行， 与CGB - / - ，CGB - /+和CGB过表达的基因修饰的小鼠系中的测量 作为选择性抑制CGB NOD功能的化合物。研究也将在我们最近进行 开发了有条件的平滑肌选择性CGB - / - 小鼠，以明确表征CGB在 平滑肌。研究将重点放在正常非高血压小鼠中发生的生理调节 然后是血管紧张素诱导的高血压。所有获得的数据将用于支持计算 建模将使我们能够预测调节CGB表达及其无代谢的影响 功能。该研究计划的完成将阐明CGB水平及其点头和SOD功能 调节O2依赖性无代谢和血管的氧化还原状态，从而提供重要见解 在正常生理和心血管疾病中调节血管张力。这些知识将领导 采用新的治疗或逆转高血压和其他心血管疾病的治疗方法。