MMI-0100 inhibits cardiac fibrosis in myocardial infarction by direct actions on cardiomyocytes and fibroblasts via MK2 inhibition.
J Mol Cell Cardiol
; 77: 86-101, 2014 Dec.
Article
en En
| MEDLINE
| ID: mdl-25257914
ABSTRACT
The cell-permeant peptide inhibitor of MAPKAP kinase 2 (MK2), MMI-0100, inhibits MK2 and downstream fibrosis and inflammation. Recent studies have demonstrated that MMI-0100 reduces intimal hyperplasia in a mouse vein graft model, pulmonary fibrosis in a murine bleomycin-induced model and development of adhesions in conjunction with abdominal surgery. MK2 is critical to the pathogenesis of ischemic heart injury as MK2(-/-) mice are resistant to ischemic remodeling. Therefore, we tested the hypothesis that inhibiting MK2 with MMI-0100 would protect the heart after acute myocardial infarction (AMI) in vivo. AMI was induced by placing a permanent LAD coronary ligation. When MMI-0100 peptide was given 30 min after permanent LAD coronary artery ligation, the resulting fibrosis was reduced/prevented ~50% at a 2 week time point, with a corresponding improvement in cardiac function and decrease in left ventricular dilation. In cultured cardiomyocytes and fibroblasts, MMI-0100 inhibited MK2 to reduce cardiomyocyte caspase 3/7 activity, while enhancing primary cardiac fibroblast caspase 3/7 activity, which may explain MMI-0100's salvage of cardiac function and anti-fibrotic effects in vivo. These findings suggest that therapeutic inhibition of MK2 after acute MI, using rationally-designed cell-permeant peptides, inhibits cardiac fibrosis and maintains cardiac function by mechanisms that involve inhibiting cardiomyocyte apoptosis, while enhancing primary cardiac fibroblast cell death.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
1_ASSA2030
/
6_ODS3_enfermedades_notrasmisibles
Problema de salud:
1_doencas_nao_transmissiveis
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6_cardiovascular_diseases
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6_ischemic_heart_disease
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6_other_respiratory_diseases
Asunto principal:
Péptidos
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Proteínas Serina-Treonina Quinasas
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Miocitos Cardíacos
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Péptidos y Proteínas de Señalización Intracelular
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Inhibidores de Proteínas Quinasas
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Fibroblastos
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Infarto del Miocardio
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
J Mol Cell Cardiol
Año:
2014
Tipo del documento:
Article