Sider Krista L, Zhu Cuilan, Kwong Andrea V, Mirzaei Zahra, de Langé Cornelius F M, Simmons Craig A
Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Toronto, Ontario, Canada, M5S 3G9.
Department of Animal and Poultry Science, University of Guelph, 50 Stone Road East, Building #70, Guelph, Ontario, Canada, N1G 2W1.
Cardiovasc Pathol. 2014 Sep-Oct;23(5):289-97. doi: 10.1016/j.carpath.2014.05.004. Epub 2014 Jun 4.
Calcific aortic valve disease (CAVD) is associated with significant cardiovascular morbidity. While late-stage CAVD is well-described, early pathobiological processes are poorly understood due to the lack of animal models that faithfully replicate early human disease. Here we evaluated a hypercholesterolemic porcine model of early diet-induced aortic valve sclerosis.
Yorkshire swine were fed either a standard or high-fat/high-cholesterol diet for 2 or 5 months. Right coronary aortic valve leaflets were excised and analyzed (immuno)histochemically.
Early human-like proteoglycan-rich onlays formed between the endothelial layer and elastic lamina in the fibrosa layer of valve leaflets, with accelerated formation associated with hypercholesterolemia (P<.05). Lipid deposition was more abundant in hypercholesterolemic swine (P<.001), but was present in a minority (28%) of onlays. No myofibroblasts, MAC387-positive macrophages, or fascin-positive dendritic cells were detected in 2-month onlays, with only scarce myofibroblasts present at 5 months. Cells that expressed osteochondral markers Sox9 and Msx2 were preferentially found in dense proteoglycan-rich onlays (P<.05) and with hypercholesterolemia (P<.05). Features of more advanced human CAVD, including calcification, were not observed in this necessarily short study.
Early aortic valve sclerosis in hypercholesterolemic swine is characterized by the formation of proteoglycan-rich onlays in the fibrosa, which can occur prior to significant lipid accumulation, inflammatory cell infiltration, or myofibroblast activation. These characteristics mimic those of early human aortic valve disease, and thus the porcine model has utility for the study of early valve sclerosis.
钙化性主动脉瓣疾病（CAVD）与严重的心血管疾病发病率相关。虽然晚期CAVD已有充分描述，但由于缺乏能忠实地复制早期人类疾病的动物模型，早期病理生物学过程仍知之甚少。在此，我们评估了一种早期饮食诱导的主动脉瓣硬化的高胆固醇血症猪模型。
将约克夏猪分别给予标准饮食或高脂/高胆固醇饮食2或5个月。切除右冠状动脉主动脉瓣小叶并进行（免疫）组织化学分析。
在瓣叶纤维层的内皮层和弹性膜之间形成了早期类似人类的富含蛋白聚糖的覆盖物，高胆固醇血症会加速其形成（P<0.05）。高胆固醇血症猪的脂质沉积更为丰富（P<0.001），但仅在少数（28%）覆盖物中出现。在2个月的覆盖物中未检测到肌成纤维细胞、MAC387阳性巨噬细胞或fascin阳性树突状细胞，5个月时仅存在少量肌成纤维细胞。表达骨软骨标记物Sox9和Msx2的细胞优先在富含蛋白聚糖的致密覆盖物中发现（P<0.05），且与高胆固醇血症有关（P<0.05）。在这项必然较短的研究中未观察到更晚期人类CAVD的特征，包括钙化。
高胆固醇血症猪的早期主动脉瓣硬化的特征是在纤维层中形成富含蛋白聚糖的覆盖物，这可能在显著脂质积累、炎症细胞浸润或肌成纤维细胞激活之前发生。这些特征与早期人类主动脉瓣疾病相似，因此该猪模型可用于早期瓣膜硬化的研究。
