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: 19-09-2017

Detalles Bibliográficos
Autor: Hamczyk, Magda Rita
Tipo de recurso: tesis doctoral
Fecha de publicación:2017
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/681832
Acceso en línea:http://hdl.handle.net/10486/681832
Access Level:acceso abierto
Palabra clave:Aterosclerosis - Tesis doctorales
Genética humana - Enfermedades - Tesis doctorales
Biología y Biomedicina / Biología
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spelling Atherosclerosis in progeria: insight from new mouse models with systemic and tissue-specific progerin expressionHamczyk, Magda RitaAterosclerosis - Tesis doctoralesGenética humana - Enfermedades - Tesis doctoralesBiología y Biomedicina / BiologíaTesis 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.Andrés, VicenteVilla Bellosta, RicardoDepartamento de BioquímicaFacultad de MedicinaCentro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) 20172017-09-19doctoral thesishttp://purl.org/coar/resource_type/c_db06NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/doctoralThesisapplication/pdfhttp://hdl.handle.net/10486/681832reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/6818322026-06-23T12:46:27Z
dc.title.none.fl_str_mv Atherosclerosis in progeria: insight from new mouse models with systemic and tissue-specific progerin expression
title Atherosclerosis in progeria: insight from new mouse models with systemic and tissue-specific progerin expression
spellingShingle Atherosclerosis in progeria: insight from new mouse models with systemic and tissue-specific progerin expression
Hamczyk, Magda Rita
Aterosclerosis - Tesis doctorales
Genética humana - Enfermedades - Tesis doctorales
Biología y Biomedicina / Biología
title_short Atherosclerosis in progeria: insight from new mouse models with systemic and tissue-specific progerin expression
title_full Atherosclerosis in progeria: insight from new mouse models with systemic and tissue-specific progerin expression
title_fullStr Atherosclerosis in progeria: insight from new mouse models with systemic and tissue-specific progerin expression
title_full_unstemmed Atherosclerosis in progeria: insight from new mouse models with systemic and tissue-specific progerin expression
title_sort Atherosclerosis in progeria: insight from new mouse models with systemic and tissue-specific progerin expression
dc.creator.none.fl_str_mv Hamczyk, Magda Rita
author Hamczyk, Magda Rita
author_facet Hamczyk, Magda Rita
author_role author
dc.contributor.none.fl_str_mv Andrés, Vicente
Villa Bellosta, Ricardo
Departamento de Bioquímica
Facultad de Medicina
Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) 
dc.subject.none.fl_str_mv Aterosclerosis - Tesis doctorales
Genética humana - Enfermedades - Tesis doctorales
Biología y Biomedicina / Biología
topic Aterosclerosis - Tesis doctorales
Genética humana - Enfermedades - Tesis doctorales
Biología y Biomedicina / Biología
description Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 19-09-2017
publishDate 2017
dc.date.none.fl_str_mv 2017
2017-09-19
dc.type.none.fl_str_mv doctoral thesis
http://purl.org/coar/resource_type/c_db06
NA
http://purl.org/coar/version/c_be7fb7dd8ff6fe43
dc.type.openaire.fl_str_mv info:eu-repo/semantics/doctoralThesis
format doctoralThesis
dc.identifier.none.fl_str_mv http://hdl.handle.net/10486/681832
url http://hdl.handle.net/10486/681832
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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