Mechanistic relationship between membrane type-1 matrix metalloproteinase and the myocardial response to pressure overload.
Circ Heart Fail
; 7(2): 340-50, 2014 Mar 01.
Article
em En
| MEDLINE
| ID: mdl-24395927
ABSTRACT
BACKGROUND:
Although matrix metalloproteinases (MMPs) were initially thought to result primarily in extracellular matrix degradation, certain MMP types, such as membrane type-1 (MT1) MMP, may also be involved in profibrotic cascades through hydrolysis of latency-associated transforming growth factor-binding protein (LTBP-1) and activation of transforming growth factor-dependent profibrotic signaling. The present study tested the hypothesis that MT1-MMP plays a direct role in the matrix remodeling response to a left ventricular (LV) pressure overload (PO) stimulus. METHODS ANDRESULTS:
Wild-type (WT) and transgenic mice with cardiac-restricted MT1-MMP overexpression or MT1-MMP reduced expression underwent PO for 4 weeks. PO resulted in a 57% increase in LV mass (no change in LV end diastolic volume, resulting in an increase in the LV mass/volume ratio consistent with concentric remodeling), a 60% increase in MT1-MMP-mediated LTBP-1 hydrolysis and a 190% increase in collagen content in WT mice. Although LV mass was similar among WT, MT1-MMP overexpression, and MT1-MMP reduced expression after PO, significant differences in LV function, MT1-MMP-mediated LTBP-1 hydrolysis, and collagen content occurred. PO in MT1-MMP overexpression increased LTBP-1 hydrolysis (18%), collagen content (60%), and left atrial dimension (19%; indicative of LV diastolic dysfunction) when compared with WT. PO in MT1-MMP reduced expression reduced left atrial dimension (19%), LTBP-1 hydrolysis (40%), and collagen content (32%) when compared with both WT.CONCLUSIONS:
Despite an equivalent PO stimulus and magnitude of LV myocardial growth, altering MT1-MMP levels caused specific matrix-dependent changes in remodeling, thereby demonstrating a mechanistic role in the development of the maladaptive remodeling and myocardial fibrotic response to PO.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
RNA
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Regulação da Expressão Gênica
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Hipertrofia Ventricular Esquerda
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Pressão Ventricular
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Remodelação Ventricular
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Metaloproteinase 14 da Matriz
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Miocárdio
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Circ Heart Fail
Ano de publicação:
2014
Tipo de documento:
Article