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

DONATO M; BUCHHOLZ B; VALDEZ L; ZAOBORNYJ T; PAEZ D; MATOSO M; AGUERO O; CHEJTMAN D; HITA A; NAVIA J; GELPI RJ; MORALES C; BARATTA SJ; VACCARINO G; TELAYNA JM; BOVERIS A

MOLECULAR AND CELLULAR BIOCHEMISTRY

SPRINGER

Lugar: Berlin; Año: 2017

0300-8177

Mol Cell Biochem. 2017 Mar 18. doi: 10.1007/s11010-017-3007-z. [Epub ahead of print]Loss of dystrophin is associated with increased myocardial stiffness in a model of left ventricular hypertrophy.Donato M1, Buchholz B1, Morales C1, Valdez L2, Zaobornyj T2, Baratta S3, Paez DT1, Matoso M1, Vaccarino G3, Chejtman D3, Agüero O3, Telayna J3, Navia J3, Hita A3, Boveris A2, Gelpi RJ4.Author informationAbstractTransition 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.KEYWORDS:Diastolic function; Dystrophin; Hypertrophy; Myocardial stiffness