Vascular Smooth Muscle and Blood Pressure Regulation By Cyb5R3²

Cyb5R3 的血管平滑肌和血压调节

基本信息

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
项目类别：
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

项目摘要

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).

【摘要】：原发性高血压的发病机制是多因素的,绝大多数的病因是案，仍不得而知。迄今为止，临床和实验证据均得出结论，减少 NO 生物利用度和/或反应性是 HTN 发病机制的一个影响因素。我们之前证明细胞色素 B5 还原酶 3 (Cyb5R3) 控制 NO 从内皮到血管的扩散平滑肌细胞（VSMC）通过调节内皮α珠蛋白血红素铁的氧化还原状态。我们现在有鉴定出 VSMC 中受 Cyb5R3 调节的另一种血红素蛋白：可溶性鸟苷酸环化酶 (sGC)，即 NO 受体。初步数据表明细胞色素 b5 还原酶 3 (Cyb5R3) 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 Cyb5R3 调节 sGC 氧化还原控制动脉血管张力和血压的状态和活动。我们将使用三个来检验这个假设具体目标：目标 1 将定义 Cyb5R3 控制 sGC 血红素还原的分子机制，目标 2 将确定 VSMC Cyb5R3 在 cGMP 信号传导中的调节作用，目标 3 将定义 SMC Cyb5R3 在血管反应性和血压控制中发挥作用。考虑 sGC 的决定性作用 NO 信号传导以及 sGC 的氧化态可以预测对新类别 sGC 的反应这一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了解生物学、精准治疗（对正确的患者使用正确的药物）和药物遗传学（基于多态性的药物选择）。