The role of hemoglobin alpha in diabetes-related vascular dysfunction

血红蛋白α在糖尿病相关血管功能障碍中的作用

• 批准号: 10297220
• 负责人: Pooneh Bagher
• 金额: $ 56.92万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10297220
• 关键词: Acute; Adrenergic Agents; Affect; Amino Acids; Arteries; Binding; Binding Sites; Biological Availability; Blood; Blood Glucose; Blood Pressure; Blood Vessels; Blood flow; Cells; Chronic; Cytoskeleton; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Diabetic mouse; Endothelial Cells; Endothelium; Enzymes; Erythrocytes; Event; Exposure to; Extracellular Matrix Proteins; Feedback; Functional disorder; Future; Genetic; Glucose; Glycosylated Hemoglobin; Glycosylated hemoglobin A; Hemoglobin; Hypertension; Hypoxia; Impairment; In Vitro; Intermittent Claudication; Knock-out; Knockout Mice; Measures; Mediating; Modification; Mus; N-terminal; NOS3 gene; Nitric Oxide; Oxides; Oxygen; Pathology; Pathway interactions; Patients; Peptides; Pharmacological Treatment; Pharmacology; Play; Process; Protein Isoforms; Proteins; Reaction; Regulation; Risk; Role; Site; Skeletal Muscle; Smooth Muscle Myocytes; Stimulus; Streptozocin; Structure; Structure of popliteal artery; Tamoxifen; Testing; Therapeutic; Tissues; Valine; Vascular Diseases; Vascular Smooth Muscle; Vasodilation; Work; blood glucose regulation; cardiovascular risk factor; constriction; cytochrome b5 reductase; diabetic; diabetic patient; genetic approach; glycation; hemoglobin B; improved; in vivo; knock-down; monomer; mouse model; novel; novel marker; novel therapeutic intervention; response; therapeutic target; vasoconstriction; wound healing

Scientific Abstract Hemoglobin, the oxygen carrying protein expressed in erythrocytes, can be glycated following elevations in blood glucose. Some amino acids, such as the N-terminal valine of the hemoglobin beta chain are highly susceptible to glycation in diabetic patients. This specific glycated isoform, termed HbA1c, has been used by clinicians as an overall picture of a diabetic patient’s ability to control their glucose over a 3-month period and as an indicator for future cardiovascular risks. Recently, it was observed that the alpha chain of hemoglobin, but not the beta chain, is expressed in endothelial cells lining arteries where it interacts with endothelial nitric oxide synthase (eNOS) to modulate nitric oxide (NO) release. Hemoglobin alpha is known to be glycated at a number of sites, including one in the putative eNOS interaction domain. Since it is well recognized that vascular dysfunction underlies many of the pathologies in diabetic patients, it was hypothesized that the hemoglobin alpha expressed in the endothelium will have aberrant function in diabetes mellitus, likely due to a glycation event. The aim of the current proposal is to examine the role of hemoglobin alpha and any possible glycated forms of hemoglobin alpha in the endothelium of a murine model of diabetes. Using pharmacological and genetic approaches, the interaction between hemoglobin alpha and eNOS will be disrupted and the influence on the development of vascular dysfunction will be explored. This work has the potential to identify both a novel biomarker of vascular risk and also a potential therapeutic target for pharmacological treatments.

科学文摘 血红蛋白是红细胞中表达的携氧蛋白，血液升高后可被糖化 葡萄糖。某些氨基酸，例如血红蛋白 β 链的 N 端缬氨酸，非常容易受到影响 对糖尿病患者的糖化作用。这种特定的糖化亚型，称为 HbA1c，已被临床医生用作 糖尿病患者在 3 个月内控制血糖能力的总体情况并作为指标 预防未来的心血管风险。最近，观察到血红蛋白的α链，而不是β链 链，在动脉内皮细胞中表达，与内皮一氧化氮合酶相互作用 (eNOS) 调节一氧化氮 (NO) 的释放。已知血红蛋白 α 在许多位点被糖化， 包括假定的 eNOS 相互作用域中的一个。由于众所周知，血管功能障碍 血红蛋白α是糖尿病患者许多病理学的基础，推测血红蛋白α表达 糖尿病患者的内皮细胞功能会出现异常，这可能是由于糖化事件所致。该组织的目标是 目前的建议是检查血红蛋白α和任何可能的糖化形式的血红蛋白的作用 糖尿病鼠模型内皮细胞中的α。利用药理学和遗传学方法， 血红蛋白 α 和 eNOS 之间的相互作用将被破坏，对发育的影响 将探讨血管功能障碍。这项工作有可能鉴定出血管的新型生物标志物 风险，也是药物治疗的潜在治疗靶点。