Loss of dystrophin is associated with increased myocardial stiffness in a model of left ventricular hypertrophy

Authors
Donato, Pablo Martín; Buchholz, Bruno; Morales, Celina; Valdez, Laura Batriz; Zaobornyj, Tamara; Baratta, Sergio; Paez, Diamela T.; Matoso, Mirian; Vaccarino, Guillermo; Chejtman, Demian; Agüero, Oscar; Telayna, Juan; Navia, José; Hita, Alejandro; Boveris, Alberto Antonio; Gelpi, Ricardo Jorge
Publication Year
2017
Language
English
Format
article
Status
Published version
Description
Transition from compensated to decompensated left ventricular hypertrophy (LVH) is accompanied by functional and structural changes. Here, the aim was to evaluate dystrophin expression in murine models and human subjects with LVH by transverse aortic constriction (TAC) and aortic stenosis (AS), respectively. We determined whether doxycycline (Doxy) prevented dystrophin expression and myocardial stiffness in mice. Additionally, ventricular function recovery was evaluated in patients 1 year after surgery. Mice were subjected to TAC and monitored for 3 weeks. A second group received Doxy treatment after TAC. Patients with AS were stratified by normal left ventricular end-diastolic wall stress (LVEDWS) and high LVEDWS, and groups were compared. In mice, LVH decreased inotropism and increased myocardial stiffness associated with a dystrophin breakdown and a decreased mitochondrial O2 uptake (MitoMVO2). These alterations were attenuated by Doxy. Patients with high LVEDWS showed similar results to those observed in mice. A correlation between dystrophin and myocardial stiffness was observed in both mice and humans. Systolic function at 1 year post-surgery was only recovered in the normal-LVEDWS group. In summary, mice and humans present diastolic dysfunction associated with dystrophin degradation. The recovery of ventricular function was observed only in patients with normal LVEDWS and without dystrophin degradation. In mice, Doxy improved MitoMVO2. Based on our results it is concluded that the LVH with high LVEDWS is associated to a degradation of dystrophin and increase of myocardial stiffness. At least in a murine model these alterations were attenuated after the administration of a matrix metalloprotease inhibitor.
Fil: Donato, Pablo Martín. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiopatología Cardiovascular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Buchholz, Bruno. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiopatología Cardiovascular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Morales, Celina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiopatología Cardiovascular; Argentina
Fil: Valdez, Laura Batriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina
Fil: Zaobornyj, Tamara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina
Fil: Baratta, Sergio. Hospital Austral; Argentina
Fil: Paez, Diamela T.. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiopatología Cardiovascular; Argentina
Fil: Matoso, Mirian. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiopatología Cardiovascular; Argentina
Fil: Vaccarino, Guillermo. Hospital Austral; Argentina
Fil: Chejtman, Demian. Hospital Austral; Argentina
Fil: Agüero, Oscar. Hospital Austral; Argentina
Fil: Telayna, Juan. Hospital Austral; Argentina
Fil: Navia, José. Hospital Austral; Argentina
Fil: Hita, Alejandro. Hospital Austral; Argentina
Fil: Boveris, Alberto Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina
Fil: Gelpi, Ricardo Jorge. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiopatología Cardiovascular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Subject
Estenosis aortica
Diastole
Ratones
Pacientes
Inmunología
Medicina Básica
CIENCIAS MÉDICAS Y DE LA SALUD
Access level
Restricted access
License
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repository
CONICET Digital (CONICET)
Institution
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identifier
oai:ri.conicet.gov.ar:11336/47390