Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology.
Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology.
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DOI：
10.1161/jaha.115.002254
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发表时间：
2015-10-27
影响因子：
5.4
通讯作者：
Masters KS
中科院分区：
文献类型：
--
作者：
Porras AM;Shanmuganayagam D;Meudt JJ;Krueger CG;Hacker TA;Rahko PS;Reed JD;Masters KS
家族性高胆固醇血症（FH）是一种常见的遗传性疾病，与动脉粥样硬化和钙化性主动脉瓣疾病（CAVD）有关。然而，在FH和非FH个体中，对高胆固醇血症在CAVD发展中的作用知之甚少。本研究使用Rapacz FH（RFH）猪（一种已建立的人FH模型）研究高胆固醇血症单独在CAVD发生和进展中的作用。RFH猪的瓣膜以前未进行过检查。从野生型（0.25岁和1岁）和RFH（0.25岁、1岁、2岁和3岁）猪中分离主动脉瓣叶。成年RFH动物表现出早期CAVD的许多特征。在成年RFH猪中发现了显著的瓣叶增厚，伴有广泛的细胞外基质重塑，包括蛋白多糖富集、胶原蛋白解体和弹性蛋白断裂。在成年RFH猪中，脂质氧化增加和巨噬细胞浸润也很明显。心内超声心动图显示一些成年RFH动物的主动脉瓣轻度硬化，但瓣膜功能未受损。成年与幼年RFH动物瓣膜的微阵列分析显示炎症相关基因显著上调，以及与动脉粥样硬化的几个共性和与人类CAVD的重叠。成年RFH猪表现出早期人类CAVD的几个特征，表明这些动物可能有助于阐明FH和非FH个体的CAVD病因。RFH猪中晚期动脉粥样硬化病变（但仅早期CAVD）的发展支持初始共享疾病过程的假设，CAVD进一步进展需要额外刺激。
Familial hypercholesterolemia (FH) is a prevalent hereditary disease associated with increased atherosclerosis and calcific aortic valve disease (CAVD). However, in both FH and non‐FH individuals, the role of hypercholesterolemia in the development of CAVD is poorly understood. This study used Rapacz FH (RFH) swine, an established model of human FH, to investigate the role of hypercholesterolemia alone in the initiation and progression of CAVD. The valves of RFH swine have not previously been examined. Aortic valve leaflets were isolated from wild‐type (0.25‐ and 1‐year‐old) and RFH (0.25‐, 1‐, 2‐, and 3‐year‐old) swine. Adult RFH animals exhibited numerous hallmarks of early CAVD. Significant leaflet thickening was found in adult RFH swine, accompanied by extensive extracellular matrix remodeling, including proteoglycan enrichment, collagen disorganization, and elastin fragmentation. Increased lipid oxidation and infiltration of macrophages were also evident in adult RFH swine. Intracardiac echocardiography revealed mild aortic valve sclerosis in some of the adult RFH animals, but unimpaired valve function. Microarray analysis of valves from adult versus juvenile RFH animals revealed significant upregulation of inflammation‐related genes, as well as several commonalities with atherosclerosis and overlap with human CAVD. Adult RFH swine exhibited several hallmarks of early human CAVD, suggesting potential for these animals to help elucidate CAVD etiology in both FH and non‐FH individuals. The development of advanced atherosclerotic lesions, but only early‐stage CAVD, in RFH swine supports the hypothesis of an initial shared disease process, with additional stimulation necessary for further progression of CAVD.