BACKGROUND Progerin, an aberrant protein that accumulates with age, causes the rare genetic disease Hutchinson-Gilford progeria syndrome (HGPS). Patients who have HGPS exhibit ubiquitous progerin expression, accelerated aging and atherosclerosis, and die in their early teens, mainly of myocardial infarction or stroke. The mechanisms underlying progerin-induced atherosclerosis remain unexplored, in part, because of the lack of appropriate animal models. METHODS We generated an atherosclerosis-prone model of HGPS by crossing apolipoprotein E-deficient (Apoe-/-) mice with LmnaG609G/G609G mice ubiquitously expressing progerin. To induce progerin expression specifically in macrophages or vascular smooth muscle cells (VSMCs), we crossed Apoe-/-LmnaLCS/LCS mice with LysMCre and SM22αCre mice, respectively. Progerin expression was evaluated by polymerase chain reaction and immunofluorescence. Cardiovascular alterations were determined by immunofluorescence and histology in male mice fed normal chow or a high-fat diet. In vivo low-density lipoprotein retention was assessed by intravenous injection of fluorescently labeled human low-density lipoprotein. Cardiac electric defects were evaluated by electrocardiography. RESULTS Apoe-/-LmnaG609G/G609G mice with ubiquitous progerin expression exhibited a premature aging phenotype that included failure to thrive and shortened survival. In addition, high-fat diet-fed Apoe-/-LmnaG609G/G609G mice developed a severe vascular pathology, including medial VSMC loss and lipid retention, adventitial fibrosis, and accelerated atherosclerosis, thus resembling most aspects of cardiovascular disease observed in patients with HGPS. The same vascular alterations were also observed in Apoe-/-LmnaLCS/LCSSM22αCre mice expressing progerin specifically in VSMCs, but not in Apoe-/-LmnaLCS/LCSLysMCre mice with macrophage-specific progerin expression. Moreover, Apoe-/-LmnaLCS/LCSSM22αCre mice had a shortened lifespan despite the lack of any overt aging phenotype. Aortas of ubiquitously and VSMC-specific progerin-expressing mice exhibited increased retention of fluorescently labeled human low-density lipoprotein, and atheromata in both models showed vulnerable plaque features. Immunohistopathological examination indicated that Apoe-/-LmnaLCS/LCSSM22αCre mice, unlike Apoe-/-LmnaG609G/G609G mice, die of atherosclerosis-related causes. CONCLUSIONS We have generated the first mouse model of progerin-induced atherosclerosis acceleration, and demonstrate that restricting progerin expression to VSMCs is sufficient to accelerate atherosclerosis, trigger plaque vulnerability, and reduce lifespan. Our results identify progerin-induced VSMC death as a major factor triggering atherosclerosis and premature death in HGPS.

中文翻译：

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在Hutchinson-Gilford早衰综合症小鼠模型中，血管平滑肌特异的Progerin表达加速了动脉粥样硬化和死亡。

背景技术早老蛋白（Progerin）是一种随着年龄增长而积累的异常蛋白质，它引起罕见的遗传疾病哈钦森-吉尔福德早衰综合症（HGPS）。患有HGPS的患者表现出普遍存在的早老蛋白表达，加速衰老和动脉粥样硬化，并在青少年早期死亡，主要是心肌梗塞或中风。早老蛋白诱导的动脉粥样硬化的潜在机制仍未探索，部分原因是缺乏合适的动物模型。方法我们通过使载脂蛋白E缺陷型（Apoe-/-）小鼠与普遍表达早老蛋白的LmnaG609G / G609G小鼠杂交，从而生成了HGPS易患动脉粥样硬化的模型。为了诱导早老蛋白在巨噬细胞或血管平滑肌细胞（VSMC）中的特异性表达，我们分别将Apoe-/-LmnaLCS / LCS小鼠与LysMCre和SM22αCre小鼠杂交。通过聚合酶链反应和免疫荧光评价早孕素的表达。通过免疫荧光法和组织学方法确定正常食物或高脂饮食的雄性小鼠的心血管变化。通过静脉内注射荧光标记的人低密度脂蛋白评估体内低密度脂蛋白保留率。通过心电图评估心脏电缺陷。结果具有普遍存在的早老蛋白表达的Apoe-/-LmnaG609G / G609G小鼠表现出过早的衰老表型，包括无法存活和缩短生存期。此外，高脂饮食喂养的Apoe-/-LmnaG609G / G609G小鼠出现了严重的血管病理，包括内侧VSMC丢失和脂质滞留，外膜纤维化和动脉粥样硬化的加速，因此类似于在HGPS患者中观察到的心血管疾病的大多数方面。在Apooe //-LmnaLCS /LCSSM22αCre小鼠中，在VSMC中特异性表达早老蛋白的小鼠中也观察到相同的血管改变，而在具有巨噬细胞特异性早老蛋白表达的Apoe-/-LmnaLCS / LCSLysMCre小鼠中未观察到相同的血管改变。此外，尽管缺乏任何明显的衰老表型，Apoe-/-LmnaLCS /LCSSM22αCre小鼠的寿命却缩短了。无处不在的和表达VSMC的早老蛋白表达小鼠的主动脉显示荧光标记的人类低密度脂蛋白的保留增加，并且在两个模型中的动脉粥样硬化均显示出易损的斑块特征。免疫组织病理学检查表明，与Apoe-/-LmnaG609G / G609G小鼠不同，Apoe-/-LmnaLCS /LCSSM22αCre小鼠死于动脉粥样硬化相关原因。结论我们已经产生了由早衰蛋白诱导的动脉粥样硬化加速的第一个小鼠模型，并证明了限制早衰蛋白表达于VSMCs足以加速动脉粥样硬化，触发斑块易损性和减少寿命。我们的研究结果表明，早衰素诱导的VSMC死亡是触发HGPS中动脉粥样硬化和过早死亡的主要因素。