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.

内皮源性一氧化氮(NO)是调节血管张力和血压的关键介质。不是 通过激活血管平滑肌中的可溶性鸟苷环化酶(SGC)来调节血管松弛。 而一氧化氮是由内皮细胞中的一氧化氮合酶合成的，而血管中一氧化氮的降解过程和 对平滑肌的新陈代谢知之甚少。血管壁中的NO降解是由O2-介导的 依赖的NO双加氧酶(NOD)，可将NO氧化为硝酸盐。细胞球蛋白(CGB)是新近发现的一种球蛋白 表达于平滑肌(但不表达于内皮细胞)，功能未知。CGB的建议是 在血管壁上作为依赖O2的NO代谢速率的关键调节器，进而调节 血管张力。在之前的授权期内：1)我们证明CGB是主要的血红素蛋白， 调节管状肌和阻力肌中氧依赖的NO代谢速率 2)我们发现细胞色素b5(B5)/b5 还原酶(B5R)构成了支持这一节点功能的主要CGB还原系统；3)我们发现 CGB具有强大的超氧化物歧化酶(SOD)功能，这是其先前未知的抗氧化剂的原因 作用；4)最近，我们发现了不损害cgb nod功能的新的选择性抑制剂。 在血管中表现出增强NO介导的sGC激活的功能。然而，主要问题是 关于血管壁不腐烂的整个过程，这在疾病中是如何变化的，以及它如何可以 被调节以减轻疾病。在这一赠款计划的下一阶段，我们寻求确定NO CGB在血管壁上的降解和SOD/抗氧化性控制着NO和氧化还原过程 正常血管和高血压血管中的代谢，以及这如何反过来调节血管张力和全身血液 压力。CGB表达水平及其结节活性调节的关键影响将是 下定决心。研究将首先在分离的血管中进行，然后在体内的心血管系统中进行， 在我们的CGB-/-、CGB-/+和CGB过表达的转基因小鼠系中进行了测量 作为选择性抑制CGB节点功能的化合物。研究也将在我们最近进行的 建立条件性平滑肌选择性CGB-/-小鼠以明确CGB在心肌梗死中的作用 平滑的肌肉。研究将集中在正常非高血压小鼠的生理调节上。 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 使我们能够预测调控CGB表达及其NO代谢的影响的模型 功能。这项研究计划的完成将阐明CGB水平及其NOD和SOD功能 调节O2依赖的NO代谢和血管的氧化还原状态，从而提供重要的见解 研究正常生理和心血管疾病中血管张力的调节。这一知识将导致 到治疗或逆转高血压和其他心血管疾病的新治疗方法。