Pharmacological inhibition of the mitochondrial NADPH oxidase 4/PKCα/Gal-3 pathway reduces left ventricular fibrosis following myocardial infarction

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 mefformin prevents adverse cardiac remodeling, as well as provides glycemic control, the underlying mechanisms remain poorly documented. This study describes the effect of mitochondria! NADPH oxidase 4 (mitoNox) and protein kinase C-alpha (PKCa) on the cardiac fibrosis and galectin 3 (Gal-3) expression. Randomly rats underwent MI, received mefformin or saline solution. A model of biomechanical strain and co-culture was used to enable cross talk between cardiomyocytes and fibroblasts. Long-term mefformin treatment after Mlwas associated with (1) a reduction in myocardial fibrosis and Gal-3 levels; (2) an increase in adenosine monophosphate-activated protein kinase (AMPK) alpha 1/alpha 2 levels; and (3) an inhibition of both mRNA expression and enzymatic activities of mitoNox and PKC alpha. These findings were replicated in the cellular model, where the silencing of AMPK expression blocked the ability of mefformin to protect cardiomyocytes from strain. The use of specific inhibitors or small interference RNA provided evidence that PKC alpha 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 mefformin-induced increase in AMPK improves myocardial remodeling post-MI, which is related to the inhibition of the mitoNox/PKC alpha/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.