Evidence of a Cardiovascular Function for Microtubule-Associated Protein Tau
Evidence of a Cardiovascular Function for Microtubule-Associated Protein Tau
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微管相关蛋白 Tau 具有心血管功能的证据
DOI：
10.3233/jad-161093
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发表时间：
2017-01-01
影响因子：
4
通讯作者：
Wright, Christine E.
中科院分区：
文献类型：
--
作者：
Betrie, Ashenafi H.;Ayton, Scott;Wright, Christine E.
Tau蛋白聚集到细胞内沉积是阿尔茨海默病(AD)等tau病的病因学特征，降低tau是正在开发的一种重要的治疗策略。然而，tau蛋白的生理功能还不是很清楚，特别是在外周。降低tau蛋白有可能扰乱其生理作用，导致不必要的影响。在这项研究中，证实了心脏组织中存在tau蛋白，并探讨了tau蛋白在心血管系统中的功能作用及其丢失的后果。用分离的13和23月龄野生型和tau缺陷型(KO)小鼠的左、右心房和肠系膜小动脉评价心血管表型。Tau KO小鼠在13个月时表现出收缩压升高和心肌肥厚，伴随着右房频率显著降低，对钙、异丙肾上腺素和交感神经电刺激的最大收缩能力轻微下降。与年轻同龄人相比，老化到23个月的tau KO小鼠导致心肌肥厚，左心房收缩能力显著减弱，血压升高，离体肠系膜动脉对血管紧张素II收缩和异丙肾上腺素松弛的敏感性。这项研究支持tau在心脏中的功能作用，这种蛋白的丢失会导致心血管功能的恶化，这种情况会随着年龄的增长而恶化。综上所述，这些结果为深入了解tau蛋白的外周功能提供了依据，并为降低tau蛋白的治疗策略提供了警告。
Aggregation of tau protein into intracellular deposits is a pathognomonic feature of tauopathies such as Alzheimer's disease (AD) and lowering tau is a prominent therapeutic strategy under development. However, the physiological function of tau protein is not well known, particularly in the periphery. Lowering tau protein risks disrupting its physiological role leading to unwanted effects. In this study, the presence of tau protein in cardiac tissue is confirmed and the functional role in the cardiovascular system and the consequences of its loss were explored. Isolated right and left atria and small mesenteric arteries from wild type and tau deficient (KO) mice of two age groups (13 and 23 months old) were used to assess cardiovascular phenotypes. Tau KO mice showed an increased systolic blood pressure and cardiac hypertrophy at 13 months, whichwas accompanied by a significantly lower right atrial rate and a subtle decrease in the maximum contractility to calcium, isoprenaline, and electrical sympathetic nerve stimulation. Aging tau KO mice to 23 months resulted in cardiac hypertrophy with significantly attenuated left atrial contractility, increased blood pressure, and sensitivity of isolated mesenteric arteries to angiotensin II contraction and isoprenaline relaxation compared to their younger counterparts. This study supports a functional role of tau in the heart and loss of this protein leads to a deterioration in cardiovascular performance which worsens with age. Taken together, these results provide insight into the peripheral function of tau protein, and give caution to the therapeutic strategy of lowering tau protein.