Abstract：
Williams-Beuren syndrome (WBS) is a rare disorder caused by a recurrent microdeletion with hallmarks of cardiovascular manifestations, mainly supra-valvular aortic stenosis (SVAS). Unfortunately, there is currently no efficient treatment. We investigated the effect of chronic oral treatment with curcumin and verapamil on the cardiovascular phenotype of a murine model of WBS harbouring a similar deletion, CD (complete deletion) mice. We analysed systolic blood pressure in vivo and the histopathology of the ascending aorta and the left ventricular myocardium to determine the effects of treatments and their underlying mechanism. Molecular analysis showed significantly upregulated xanthine oxidoreductase (XOR) expression in the aorta and left ventricular myocardium of CD mice. This overexpression is concomitant with increased levels of nitrated proteins as a result of byproduct-mediated oxidative stress damage, indicating that XOR-generated oxidative stress impacts the pathophysiology of cardiovascular manifestations in WBS. Only the combined therapy of curcumin and verapamil resulted in a significant improvement of cardiovascular parameters via activation of the nuclear factor erythroid 2 (NRF2) and reduction of XOR and nitrated protein levels. Our data suggested that the inhibition of XOR and oxidative stress damage could help prevent the severe cardiovascular injuries of this disorder.
摘要：
Williams-Beuren综合征（WBS）是一种罕见的疾病，由具有心血管表现特征的复发性微缺失引起，主要是瓣膜上主动脉瓣狭窄（SVAS）。不幸的是,目前没有有效的治疗方法。我们研究了姜黄素和维拉帕米的慢性口服治疗对具有相似缺失的WBS小鼠模型的心血管表型的影响。CD(完全缺失)小鼠。我们分析了体内收缩压以及升主动脉和左心室心肌的组织病理学，以确定治疗的效果及其潜在机制。分子分析显示，CD小鼠主动脉和左心室心肌中黄嘌呤氧化还原酶（XOR）的表达显着上调。这种过度表达伴随着硝化蛋白水平的增加，这是副产物介导的氧化应激损伤的结果。表明XOR产生的氧化应激影响WBS中心血管表现的病理生理学。只有姜黄素和维拉帕米的联合治疗才能通过激活核因子红细胞2（NRF2）和降低XOR和硝化蛋白水平显着改善心血管参数。我们的数据表明，抑制XOR和氧化应激损伤可以帮助预防这种疾病的严重心血管损伤。
