Pharmacological inhibition of the mitochondrial NADPH oxidase 4/PKCα/Gal-3 pathway reduces left ventricular fibrosis following myocardial infarction.
Transl Res
; 199: 4-23, 2018 09.
Article
en En
| MEDLINE
| ID: mdl-29753686
ABSTRACT
Although the initial reparative fibrosis after myocardial infarction (MI) is crucial for preventing rupture of the ventricular wall, an exaggerated fibrotic response and reactive fibrosis outside the injured area are detrimental. Although metformin prevents adverse cardiac remodeling, as well as provides glycemic control, the underlying mechanisms remain poorly documented. This study describes the effect of mitochondrial NADPH oxidase 4 (mitoNox) and protein kinase C-alpha (PKCα) on the cardiac fibrosis and galectin 3 (Gal-3) expression. Randomly rats underwent MI, received metformin or saline solution. A model of biomechanical strain and co-culturewas used to enable cross talk between cardiomyocytes and fibroblasts. Long-term metformin treatment after MIwas associated with (1) a reduction in myocardial fibrosis and Gal-3 levels; (2) an increase in adenosine monophosphate-activated protein kinase (AMPK) α1/α2 levels; and (3) an inhibition of both mRNA expression and enzymatic activities of mitoNox and PKCα. These findings were replicated in the cellular model, where the silencing of AMPK expression blocked the ability of metformin to protect cardiomyocytes from strain. The use of specific inhibitors or small interference RNA provided evidence that PKCα is downstream of mitoNox, and that the activation of this pathway results in Gal-3 upregulation.The Gal-3 secreted by cardiomyocytes has a paracrine effect on cardiac fibroblasts, inducing their activation. In conclusion, a metformin-induced increase in AMPK improves myocardial remodeling post-MI, which is related to the inhibition of the mitoNox/PKCα/Gal-3 pathway. Manipulation of this pathway might offer new therapeutic options against adverse cardiac remodeling, in terms of preventing the activation of the present fibroblast population.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
NADPH Oxidasas
/
Remodelación Ventricular
/
Galectina 3
/
Proteína Quinasa C-alfa
/
Ventrículos Cardíacos
/
Metformina
/
Mitocondrias Cardíacas
/
Infarto del Miocardio
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Transl Res
Asunto de la revista:
MEDICINA
/
TECNICAS E PROCEDIMENTOS DE LABORATORIO
Año:
2018
Tipo del documento:
Article
País de afiliación:
España