Atherosclerosis in progeria: insight from new mouse models with systemic and tissue-specific progerin expression

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 19-09-2017Esta tesis tiene embargado el acceso al texto completo hasta el 19-03-2019Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide due to the progressive aging of our societies. Age-related decline in cardiovascular health is accelerated in a rare genetic disorder called Hutchinson-Gilford progeria syndrome (HGPS). The disease is caused by a de novo point mutation in the LMNA gene, which leads to the expression of “progerin”, a mutant form of the nuclear protein lamin A. Since lamin A possesses important structural and functional properties, progerin expression triggers numerous nuclear abnormalities. Children with HGPS exhibit premature aging symptoms, including alopecia, osteoporosis, lipodystrophy, joint stiffness, and skin wrinkling and mottling. However, the most clinically relevant feature of the disease is accelerated atherosclerosis, which leads to premature death at an average age of 14.6 years, predominantly from myocardial infarction or stroke. The mechanisms through which progerin provokes enhanced atherosclerosis remain poorly understood, in part due to the paucity of suitable models. To address this, we sought to generate new mouse models that allow the study of atherosclerosis in the context of HGPS. When compared with control mice expressing wild-type lamin A/C, mice with ubiquitous progerin expression exhibited a premature aging phenotype, including reduced body weight and shortened survival. In addition, progerin-expressing mice showed increased atherosclerosis burden together with a severe vascular pathology, including the depletion of vascular smooth muscle cells (VSMCs), increased collagen content, medial lipid retention and adventitial fibrosis, resembling most aspects of CVD observed in HGPS. We also found that mice expressing progerin specifically in VSMCs, but not in macrophages, fully recapitulated the vascular pathology observed in the ubiquitous progeria model. Atheromas of both ubiquitous and VSMC-specific models showed evidence of plaque disruption, which might lead to myocardial infarction. Using a transcriptomic approach, we identified endoplasmic reticulum (ER) stress and the unfolded protein response as possible driver mechanisms of progerin-induced VSMC death and accelerated atherosclerosis. Accordingly, treatment with tauroursodeoxycholic acid (TUDCA), a chemical chaperone that increases the capacity of a cell to sustain ER stress, was effective at ameliorating vascular disease (atherosclerosis, VSMC loss and adventitial thickening) in both ubiquitous and VSMC-specific mouse models. TUDCA also prolonged the survival of mice with VSMC-specific progerin expression by 35%. Taken together, these findings indicate that TUDCA may be effective in the treatment of atherosclerosis and associated cardiovascular events in HGPS. Moreover, since progerin accumulates with age in non-HPGS individuals, our data may also shed some light on the mechanisms of normal aging