■弹性假性黄瘤(PXE)是由Abcc6基因突变引起的多系统遗传性疾病。该疾病的特征是皮肤异位矿化,眼睛,和动脉血管.先前的研究表明,PXE患者的心血管并发症部分是由过早的动脉粥样硬化引起的。这项研究的目的是确定动脉粥样硬化饮食对异位矿化的影响。
■我们使用Abcc6tm1JfK小鼠(Abcc6-/-小鼠)作为已建立的PXE临床前模型。将4周龄的后代分为两组,并饲喂标准对照实验室饮食(对照组)和致动脉粥样硬化饮食。测量血清脂质谱和胆汁酸,通过组织病理学分析和化学钙定量分析评估脂肪变性和组织矿化,分别。
■喂食致动脉粥样硬化饮食50-58周后,总胆固醇的浓度,低密度脂蛋白/极低密度脂蛋白胆固醇,在致动脉粥样硬化饮食的Abcc6-/-小鼠中胆汁酸明显升高(180.9±14.8g/L,145.9±12.9g/L,和9.7±1.4μmol/L,分别)比对照饮食的Abcc6-/-小鼠(85.2±4.8g/L,25.1±5.5g/L,3.3±0.5μmol/L,分别)(P<0.001)。高胆固醇血症伴随着肝脏和主动脉中广泛的脂质积累,脂肪变性的特征。直接钙测定表明,含有vibrisae真皮鞘的枪口皮肤的矿化显着增加(致动脉粥样硬化饮食为57.2±4.4μmolCa/g组织,对照饮食为43.9±2.2μmolCa/g组织;P<0.01),这些小鼠异位矿化过程的可重复生物标志物。在动脉粥样化饮食的小鼠的肾脏和眼睛中也观察到矿化频率增加(P<0.01)。
■这些观察结果表明,致动脉粥样硬化的饮食导致Abcc6-/-小鼠的高胆固醇血症和加速的异位矿化。我们的发现对PXE患者有临床意义,一种目前难以治疗的疾病,具有相当高的发病率和偶尔的死亡率。
UNASSIGNED: Pseudoxanthoma elasticum (PXE) is a multisystem heritable disorder caused by mutations in the Abcc6 gene. The disease is characterized by ectopic mineralization of the skin, eyes, and arterial blood vessels. Previous studies have suggested that cardiovascular complications in patients with PXE are caused in part by premature atherosclerosis. The aim of this study is to determine the effect of an atherogenic diet on ectopic mineralization.
UNASSIGNED: We used Abcc6 tm1JfK mice (Abcc6 -/- mice) as an established preclinical model of PXE. The offspring at age of 4 weeks were divided into two groups and fed the standard control laboratory diet (control group) and the atherogenic diet. Serum lipid profiles and bile acids were measured, and steatosis and tissue mineralization were evaluated by histopathologic analysis and chemical calcium quantification assay, respectively.
UNASSIGNED: After 50-58 weeks of feeding an atherogenic diet, the concentrations of total cholesterol, low-density lipoprotein/very-low-density lipoprotein cholesterol, and bile acids were significantly higher in the Abcc6 -/- mice on the atherogenic diet (180.9 ± 14.8 g/L, 145.9 ± 12.9 g/L, and 9.7 ± 1.4 μmol/L, respectively) than in Abcc6 -/- mice on a control diet (85.2 ± 4.8 g/L, 25.1 ± 5.5 g/L, and 3.3 ± 0.5 μmol/L, respectively) (P < 0.001). Hypercholesterolemia was accompanied by extensive lipid accumulation in the liver and aorta, a characteristic feature of steatosis. The direct calcium assay demonstrated significantly increased mineralization of the muzzle skin containing the dermal sheath of vibrissae (57.2 ± 4.4 μmol Ca/gram tissue on the atherogenic diet and 43.9 ± 2.2 μmol Ca/gram tissue on control diet; P < 0.01), a reproducible biomarker of the ectopic mineralization process in these mice. An increased frequency of mineralization was also observed in the kidneys and eyes of mice on the atherogenic diet (P < 0.01).
UNASSIGNED: These observations suggest that the atherogenic diet caused hypercholesterolemia and accelerated ectopic mineralization in the Abcc6 -/- mice. Our findings have clinical implications for patients with PXE, a currently intractable disorder with considerable morbidity and occasional mortality.