Vascular Smooth Muscle-Specific Progerin Expression Accelerates Atherosclerosis and Death in a Mouse Model of Hutchinson-Gilford Progeria Syndrome.
Vascular Smooth Muscle-Specific Progerin Expression Accelerates Atherosclerosis and Death in a Mouse Model of Hutchinson-Gilford Progeria Syndrome.
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DOI：
10.1161/circulationaha.117.030856
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发表时间：
2018-07-17
期刊：
影响因子：
37.8
通讯作者：
Andrés V
中科院分区：
文献类型：
--
作者：
Hamczyk MR;Villa-Bellosta R;Gonzalo P;Andrés-Manzano MJ;Nogales P;Bentzon JF;López-Otín C;Andrés V
文本中提供了补充数字内容。早衰蛋白是一种随着年龄的增长而积累的异常蛋白，会导致罕见的遗传病哈钦森-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素表达、加速衰老和动脉粥样硬化，并在十几岁时死亡，主要死于心肌梗塞或中风。早老素诱导的动脉粥样硬化的机制仍未被探索，部分原因是缺乏合适的动物模型。我们通过将载脂蛋白 E 缺陷 (Apoe–/–) 小鼠与普遍表达早老素的 LmnaG609G/G609G 小鼠杂交，生成了易发生动脉粥样硬化的 HGPS 模型。为了诱导巨噬细胞或血管平滑肌细胞 (VSMC) 中特异的早老素表达，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估早老素表达。通过免疫荧光和组织学测定喂食正常食物或高脂肪饮食的雄性小鼠的心血管变化。通过静脉注射荧光标记的人低密度脂蛋白来评估体内低密度脂蛋白保留。通过心电图评估心脏电缺陷。普遍表达早老素的 Apoe–/–LmnaG609G/G609G 小鼠表现出过早衰老的表型，包括发育迟缓和生存期缩短。此外，高脂饮食喂养的 Apoe–/–LmnaG609G/G609G 小鼠出现了严重的血管病理学，包括内侧 VSMC 丢失和脂质滞留、外膜纤维化和加速动脉粥样硬化，因此与 HGPS 患者中观察到的心血管疾病的大部分方面相似。在 VSMC 中特异表达早衰素的 Apoe–/–LmnaLCS/LCSLysMCre 小鼠中也观察到了相同的血管变化，但在巨噬细胞特异性早衰素表达的 Apoe–/–LmnaLCS/LCSLysMCre 小鼠中却没有观察到。此外，Apoe–/–LmnaLCS/LCSSM22αCre 小鼠尽管没有任何明显的衰老表型，但寿命缩短。普遍表达 VSMC 特异性早老蛋白的小鼠的主动脉表现出荧光标记的人低密度脂蛋白的保留增加，并且两种模型中的动脉粥样硬化斑块均表现出易损斑块特征。免疫组织病理学检查表明，Apoe–/–LmnaLCS/LCSSM22αCre 小鼠与 Apoe–/–LmnaG609G/G609G 小鼠不同，死于动脉粥样硬化相关原因。我们已经建立了第一个早老蛋白诱导的动脉粥样硬化加速的小鼠模型，并证明限制早老蛋白在 VSMC 中的表达足以加速动脉粥样硬化，引发斑块脆弱性并缩短寿命。我们的研究结果表明，早老素诱导的 VSMC 死亡是 HGPS 中引发动脉粥样硬化和过早死亡的主要因素。
Supplemental Digital Content is available in the text. 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. 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. 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. 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.