Biglycan deficiency causes spontaneous aortic dissection and rupture in mice
Biglycan deficiency causes spontaneous aortic dissection and rupture in mice
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DOI：
10.1161/circulationaha.106.653980
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发表时间：
2007-05-29
期刊：
影响因子：
37.8
通讯作者：
Bianco, Paolo
中科院分区：
文献类型：
--
作者：
Heegaard, Anne-Marie;Corsi, Alessandro;Bianco, Paolo
背景-对于大多数病例，自发性主动脉夹层和破裂的原因尚不清楚。遗传风险与马凡氏综合征、Ehlers-Danlos综合征IV型和定位于不同常染色体的基因座相关。然而，对谱系的分析表明，它也可能作为X连锁性状遗传。双糖链蛋白聚糖基因，在人类和小鼠的X染色体上发现，编码一种小的富含亮氨酸的蛋白聚糖，参与细胞外基质的完整性。血管表型从来没有被描述在小亮氨酸丰富的蛋白聚糖基因缺陷的小鼠。在繁殖的BALB/cA小鼠纯合子的一个无效突变的biglycan基因，我们观察到，50%的biglycan缺陷的雄性小鼠突然死亡的前3个月的life.Methods和结果-尸检发现一个重大出血在胸腔或腹腔，和组织学显示主动脉破裂，涉及内膜和中层撕裂，以及夹层之间的媒体和外膜。通过透射电子显微镜和生物力学测试，双糖蛋白聚糖缺陷小鼠的椎间盘显示胶原纤维结构异常和抗张强度降低。在雄性和雌性双糖链聚糖缺陷小鼠中观察到类似的胶原原纤维变化，这意味着额外的决定因素，如性别相关的应激反应，在这种血管灾难的发展中只在雄性小鼠中发挥作用。主动脉破裂的缺陷雄性小鼠暗示双糖链蛋白聚糖对主动脉壁的结构和功能完整性至关重要，并提示双糖链蛋白聚糖基因缺陷在人类主动脉夹层和破裂发病机制中的潜在作用
Background - For the majority of cases, the cause of spontaneous aortic dissection and rupture is unknown. An inherited risk is associated with Marfan syndrome, Ehlers-Danlos syndrome type IV, and loci mapped to diverse autosomal chromosomes. Analysis of pedigrees however has indicated that it may be also inherited as an X-linked trait. The biglycan gene, found on chromosome X in humans and mice, encodes a small leucine- rich proteoglycan involved in the integrity of the extracellular matrix. A vascular phenotype has never been described in mice deficient in the gene for small leucine-rich proteoglycans. In the breeding of BALB/cA mice homozygous for a null mutation of the biglycan gene, we observed that 50% of biglycan- deficient male mice died suddenly within the first 3 months of life.Methods and Results - Necropsies revealed a major hemorrhage in the thoracic or abdominal cavity, and histology showed aortic rupture that involved an intimal and medial tear as well as dissection between the media and adventitia. By transmission electron microscopy and biomechanical testing, the aortas of biglycan-deficient mice showed structural abnormalities of collagen fibrils and reduced tensile strength. Similar collagen fibril changes were observed in male as well as in female biglycan-deficient mice, which implies a role of additional determinants such as gender- related response to stress in the development of this vascular catastrophe only in male mice.Conclusions - The spontaneous death of biglycan-deficient male mice from aortic rupture implicates biglycan as essential for the structural and functional integrity of the aortic wall and suggests a potential role of biglycan gene defects in the pathogenesis of aortic dissection and rupture in humans.