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 通过激活平滑肌中的可溶性鸟苷酸环化酶 (sGC) 介导血管舒张。 虽然NO是由内皮细胞中的NO合成酶合成的，但血管内NO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 依赖型一氧化氮双加氧酶（NOD），将一氧化氮氧化成硝酸盐。细胞珠蛋白（Cgb）是最近发现的一种球蛋白 在平滑肌中表达（但不在内皮中表达），其功能以前未知。建议 Cgb 作为血管壁中 O2 依赖性 NO 代谢速率的关键调节因子，进而调节 血管张力。在之前的资助期内：1) 我们证明了 Cgb 是主要的血红素蛋白 调节导管和阻力平滑肌中 O2 依赖性 NO 代谢速率 血管，进而深刻调节血管张力； 2) 我们鉴定出细胞色素 b5 (B5)/ B5 还原酶 (B5R) 构成支持此 NOD 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，这是其先前无法解释的抗氧化剂的原因 影响； 4) 最近，我们发现了 Cgb NOD 功能的新型选择性抑制剂，不会损害其 SOD 功能，并在血管中显示可增强 NO 介导的 sGC 激活。然而，主要问题 仍然关注血管壁中 NO 衰变的整个过程，这在疾病中如何变化，以及它如何影响 进行调节以改善疾病。在本资助计划的下一阶段，我们寻求确定 NO 如何 血管壁中 Cgb 的降解和 SOD/抗氧化特性控制着 NO 和氧化还原过程 正常血管和高血压血管的新陈代谢，以及它如何调节血管张力和全身血液 压力。 Cgb 表达水平及其 NOD 活性调节的关键影响将是 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， 在我们的 Cgb-/-、Cgb-/+ 和 Cgb 过度表达的转基因小鼠品系中进行测量 作为选择性抑制 Cgb NOD 功能的化合物。我们最近也将进行研究 开发了条件平滑肌选择性 Cgb-/- 小鼠，以明确表征 Cgb 在 平滑肌。研究将集中于正常非高血压小鼠的生理调节 然后是血管紧张素诱发的高血压。获得的所有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 NO 代谢的影响 功能。该研究计划的完成将阐明 Cgb 水平及其 NOD 和 SOD 功能如何 调节 O2 依赖性 NO 代谢和血管的氧化还原状态，从而提供重要的见解 参与正常生理和心血管疾病中血管张力的调节。这些知识将引导 治疗或逆转高血压和其他心血管疾病的新治疗方法。