Vascular Smooth Muscle and Blood Pressure Regulation By Cyb5R3²

Cyb5R3 的血管平滑肌和血压调节

• 批准号: 9921478
• 负责人: Adam Carl Straub
• 金额: $ 39.1万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9921478
• 关键词: Adult; Affect; African American; Arteries; Biochemical; Biological Availability; Biology; Biosensor; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Clinical; Critical Pathways; Cyclic GMP; Cytochrome a; Data; Diffusion; Endothelium; Erythrocytes; Essential Hypertension; Etiology; Experimental Models; Gene Frequency; Generations; Genetic; Genetic Polymorphism; Guanosine Monophosphate; Heart; Heme; Heme Iron; Hemeproteins; Human; Hyperplasia; Impairment; Kinetics; Knockout Mice; Link; LoxP-flanked allele; Measures; Mediating; Medicine; Mesentery; Methemoglobin; Molecular; Morbidity - disease rate; Mus; Nitric Oxide; Organ; Oxidases; Oxidation-Reduction; Oxides; Oxidoreductase; Pathogenesis; Pathogenicity; Patient Rights; Periodicity; Peroxidases; Pharmaceutical Preparations; Pharmacogenetics; Pharmacology; Phenotype; Point Mutation; Precision therapeutics; Production; Proteins; Rattus; Reaction; Reactive Oxygen Species; Regulation; Resistance; Risk Factors; Role; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Soluble Guanylate Cyclase; Spectrophotometry; Systemic hypertension; Tamoxifen; Techniques; Testing; Time; United States; Vascular Smooth Muscle; Vascular remodeling; Vasoconstrictor Agents; Vasodilator Agents; Wild Type Mouse; alpha Globin; base; blood pressure regulation; cardiovascular risk factor; cell type; cytochrome b5 reductase; design; gain of function; hemodynamics; in vitro Assay; iron (III) reductase; knock-down; loss of function; mimetics; novel; oxidation; predicting response; protein protein interaction; response; vasoconstriction

Abstract: The pathogenesis of essential hypertension is multifactorial and the etiology, in a vast majority of cases, remains unknown. To date, both clinical and experimental evidence concludes that reduced NO bioavailability and/or responsiveness is a contributing factor in the pathogenesis of HTN. We previously demonstrated that cytochrome B5 reductase 3 (Cyb5R3) controls NO diffusion from endothelium to vascular smooth muscle cells (VSMC) by regulation of endothelial alpha globin heme iron redox state. We have now identified an additional heme protein regulated by Cyb5R3 in VSMC: soluble guanylyl cyclase (sGC), the NO receptor. Preliminary data demonstrates that cytochorome b5 reductase 3 (Cyb5R3) regulates sGC function, NO signal transduction, cyclic guanosine monophosphate (cGMP) levels, arterial tone and blood pressure by regulating sGC heme iron redox state. Our overarching hypothesis states that Cyb5R3 regulates sGC redox state and activity to control arterial vascular tone and blood pressure. We will test this hypothesis using three specific aims: Aim 1 will define the molecular mechanisms by which Cyb5R3 controls sGC heme reduction, Aim 2 will determine the regulatory role of VSMC Cyb5R3 in cGMP signaling and Aim 3 will define the role of SMC Cyb5R3 function in vascular reactivity and blood pressure control. Considering the defining role of sGC in NO signaling and the fact that the oxidation state of sGC may predict responses to new classes of sGC activator and stimulator medications, we anticipate that these studies may significantly impact our understanding of biology, precision therapeutics (right drug for the right patient) and pharmacogenetics (polymorphism based drug selection).

翻译后摘要：原发性高血压的发病机制是多因素和病因，在绝大多数 案件仍然未知。迄今为止，临床和实验证据都得出结论，减少NO 生物利用度和/或反应性是HTN发病机制中的一个促成因素。我们之前 证明细胞色素B5还原酶3（Cyb 5 R3）控制NO从内皮扩散到血管 平滑肌细胞（VSMC）通过调节内皮α珠蛋白血红素铁氧化还原状态。我们现在已经 在VSMC中发现了另外一种受Cyb 5 R3调控的血红素蛋白：可溶性鸟苷酸环化酶（sGC），NO 受体的初步数据表明，细胞色素b5还原酶3（Cyb 5 R3）调节sGC功能， NO信号转导、环磷酸鸟苷（cGMP）水平、动脉张力和血压。 调节sGC血红素铁氧化还原状态。我们的总体假设表明Cyb 5 R3调节sGC氧化还原 控制动脉血管张力和血压的状态和活动。我们将用三个例子来检验这个假设。 具体目标：目标1将定义Cyb 5 R3控制sGC血红素还原的分子机制， 目的2将确定VSMC Cyb 5 R3在cGMP信号传导中的调节作用，目的3将确定Cyb 5 R3在cGMP信号传导中的作用。 SMC Cyb 5 R3在血管反应性和血压控制中起作用。考虑到sGC的决定性作用 以及sGC的氧化态可以预测对新类型sGC的反应的事实 激活剂和刺激剂药物，我们预计这些研究可能会显着影响我们的 了解生物学，精确治疗（为正确的患者提供正确的药物）和药物遗传学 （基于多态性的药物选择）。