Loss of dystrophin is associated with increased myocardial stiffness in a model of left ventricular hypertrophy.
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 O2uptake (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.
Department of Pathology, Faculty of Medicine, Institute of Cardiovascular Pathophysiology, University of Buenos Aires, J. E. Uriburu 950, 2nd floor, C1114AAD, Buenos Aires, Argentina.
Martín
M
Donato
Department of Pathology, Faculty of Medicine, Institute of Cardiovascular Pathophysiology, University of Buenos Aires, J. E. Uriburu 950, 2nd floor, C1114AAD, Buenos Aires, Argentina.
Bruno
B
Buchholz
Department of Pathology, Faculty of Medicine, Institute of Cardiovascular Pathophysiology, University of Buenos Aires, J. E. Uriburu 950, 2nd floor, C1114AAD, Buenos Aires, Argentina.
Celina
C
Morales
School of Pharmacy and Biochemistry, Institute of Biochemistry and Molecular Medicine, University of Buenos Aires-CONICET, Buenos Aires, Argentina.
Laura
L
Valdez
School of Pharmacy and Biochemistry, Institute of Biochemistry and Molecular Medicine, University of Buenos Aires-CONICET, Buenos Aires, Argentina.
Tamara
T
Zaobornyj
Institute of Cardiology and Cardiovascular Therapeutic, Austral Hospital, Buenos Aires, Argentina.
Sergio
S
Baratta
Department of Pathology, Faculty of Medicine, Institute of Cardiovascular Pathophysiology, University of Buenos Aires, J. E. Uriburu 950, 2nd floor, C1114AAD, Buenos Aires, Argentina.
Diamela T
DT
Paez
Department of Pathology, Faculty of Medicine, Institute of Cardiovascular Pathophysiology, University of Buenos Aires, J. E. Uriburu 950, 2nd floor, C1114AAD, Buenos Aires, Argentina.
Mirian
M
Matoso
Institute of Cardiology and Cardiovascular Therapeutic, Austral Hospital, Buenos Aires, Argentina.
Guillermo
G
Vaccarino
Institute of Cardiology and Cardiovascular Therapeutic, Austral Hospital, Buenos Aires, Argentina.
Demian
D
Chejtman
Institute of Cardiology and Cardiovascular Therapeutic, Austral Hospital, Buenos Aires, Argentina.
Oscar
O
Agüero
Institute of Cardiology and Cardiovascular Therapeutic, Austral Hospital, Buenos Aires, Argentina.
Juan
J
Telayna
Institute of Cardiology and Cardiovascular Therapeutic, Austral Hospital, Buenos Aires, Argentina.
José
J
Navia
Institute of Cardiology and Cardiovascular Therapeutic, Austral Hospital, Buenos Aires, Argentina.
Alejandro
A
Hita
School of Pharmacy and Biochemistry, Institute of Biochemistry and Molecular Medicine, University of Buenos Aires-CONICET, Buenos Aires, Argentina.
Alberto
A
Boveris
Department of Pathology, Faculty of Medicine, Institute of Cardiovascular Pathophysiology, University of Buenos Aires, J. E. Uriburu 950, 2nd floor, C1114AAD, Buenos Aires, Argentina. rgelpi@fmed.uba.ar.
Ricardo J
RJ
Gelpi
D000818:Animals; D004195:Disease Models, Animal; D004318:Doxycycline / Q000009:adverse effects / Q000494:pharmacology; D016189:Dystrophin / Q000172:deficiency*; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D059748:Proteolysis
D016189:Dystrophin; D004318:Doxycycline
Diastolic function; Dystrophin; Hypertrophy; Myocardial stiffness