The role of hemoglobin alpha in diabetes-related vascular dysfunction

科学抽象 血红蛋白是在红细胞中表达的携氧蛋白，在血液中血红蛋白水平升高后可被糖化。 葡萄糖某些氨基酸，如血红蛋白β链的N-末端缬氨酸， 糖尿病患者的糖基化。这种特定的糖化亚型，称为HbA 1c，已被临床医生用作 糖尿病患者在3个月内控制血糖的能力的总体情况， 未来的心血管风险。最近，人们观察到血红蛋白的α链，而不是β链 链在动脉内皮细胞中表达，并与内皮型一氧化氮合酶相互作用 （eNOS）来调节一氧化氮（NO）释放。已知血红蛋白α在许多位点被糖化， 包括一个在推定的eNOS相互作用结构域中。由于血管功能障碍 是糖尿病患者许多病理的基础，假设血红蛋白α表达 在糖尿病中可能由于糖化事件而具有异常功能。的目的 目前的建议是研究血红蛋白α和任何可能的糖化血红蛋白形式的作用 糖尿病小鼠模型内皮细胞中的α。使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， 将探索血管功能障碍。这项工作有可能确定一种新的血管生物标志物， 风险，也是药理学治疗的潜在治疗靶点。

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.