Vascular Smooth Muscle–Specific Progerin Expression Accelerates Atherosclerosis and Death in a Mouse Model of Hutchinson-Gilford Progeria Syndrome

• DOI: 10.1161/circulationaha.117.030856
• Publication Date: 2018-02-28T10:25:11Z
• Authors: Magda R. Hamczyk; Ricardo Villa-Bel...; Pilar Gonzalo; María J. Andrés-M...; Paula Nogales; Jacob F. Bentzon; Carlos López-Otín; Vicente Andrés
• Keywords: Progeria

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