The role of hemoglobin alpha in diabetes-related vascular dysfunction

《科学文摘》 血红蛋白是一种在红细胞中表达的携氧蛋白，在血液中升高后可以糖化。 葡萄糖。某些氨基酸，如血红蛋白β链的N-末端的缬氨酸，是高度敏感的 糖尿病患者的糖基化。这种特殊的糖化异构体，称为HbA1c，已被临床医生用作 糖尿病患者在3个月内控制血糖的能力的总体情况，并作为一个指标 以应对未来的心血管风险。最近，人们观察到，血红蛋白的阿尔法链，而不是β链 链在动脉内皮细胞中表达，在那里它与内皮型一氧化氮合酶相互作用 (ENOS)调节一氧化氮(NO)的释放。已知的是，血红蛋白α在许多位置糖化， 包括在推测的eNOS相互作用域中的一个。因为大家都知道血管功能障碍 在糖尿病患者的许多病理基础上，人们假设血红蛋白α表达 在糖尿病时，内皮细胞的功能会发生异常，这可能是由于糖基化事件所致。该计划的目的是 目前的建议是研究血红蛋白α和任何可能的糖化形式的血红蛋白的作用。 糖尿病小鼠模型血管内皮细胞中的α蛋白。使用药理学和遗传学方法， 血红蛋白α与eNOS之间的相互作用将被破坏，并对糖尿病的发生发展产生影响 我们将探讨血管功能障碍。这项工作有可能识别出一种新的血管生物标记物 这是一种风险，也是药物治疗的潜在治疗目标。

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.