Metformin Inhibits Angiotensin II-Induced Differentiation of Cardiac Fibroblasts into Myofibroblasts

Abstract

Differentiation of cardiac fibroblasts into myofibroblasts is a critical event in the progression of cardiac fibrosis that leads to pathological cardiac remodeling. Metformin, an antidiabetic agent, exhibits a number of cardioprotective properties. However, much less is known regarding the effect of metformin on cardiac fibroblast differentiation. Thus, in the present study, we examined the effect of metformin on angiotensin (Ang) II-induced differentiation of cardiac fibroblasts into myofibroblasts and its underlying mechanism. Adult rat cardiac fibroblasts were stimulated with Ang II (100 nM) in the presence or absence of metformin (10–200 µM). Ang II stimulation induced the differentiation of cardiac fibroblasts into myofibroblasts, as indicated by increased expression of α-smooth muscle actin (α-SMA) and collagen types I and III, and this effect of Ang II was inhibited by pretreatment of cardiac fibroblasts with metformin. Metformin also decreased Ang II-induced reactive oxygen species (ROS) generation in cardiac fibroblasts via inhibiting the activation of the PKC-NADPH oxidase pathway. Further experiments using PKC inhibitor calphostin C and NADPH oxidase inhibitor apocynin confirmed that inhibition of the PKC-NADPH oxidase pathway markedly attenuated Ang II-induced ROS generation and myofibroblast differentiation. These data indicate that metformin inhibits Ang II-induced myofibroblast differentiation by suppressing ROS generation via the inhibition of the PKC-NADPH oxidase pathway in adult rat cardiac fibroblasts. Our results provide new mechanistic insights regarding the cardioprotective effects of metformin and provide an efficient therapeutic strategy to attenuate cardiac fibrosis.

Metformin: From Mechanisms of Action to Therapies

“…Similar results were obtained in mice subjected to left ventricular pressure overload by transverse aortic constriction even if, in this case, AMPK did not seem to be involved (Xiao et al, 2010). In other studies, it has been established that metformin inhibits myofibroblast differentiation by suppressing ROS generation via the inhibition of the NADPH oxidase pathway (Bai et al, 2013), AMPK probably mediating this effect. Of note, a genetic link between AMPK and cardiac fibrosis has been recently demonstrated in a myocardial infarction mouse model (Noppe et al, 2014).…”

Arrhythmogenic gene remodelling in elderly patients with type 2 diabetes with aortic stenosis and normal left ventricular ejection fraction

“…Likewise, given that metformin has wide‐ranging effects on growth factors and an antifibrotic effect (Bai et al . ), some reduction in the gene expression changes we may have seen in the study could have occurred.…”

“…One area of potential limitation is in the medication background of our diabetes group, as sulphonylureas have been shown to have some effect on the cardiac ATP-dependent K + channel (Aronson et al 2003), and although this channel was not assessed in the present study, some overlap with the other K + channel genes studied here cannot be excluded. Likewise, given that metformin has wide-ranging effects on growth factors and an antifibrotic effect (Bai et al 2013), some reduction in the gene expression changes we may have seen in the study could have occurred.…”

Response to the Paper by nlR et al. Entitled ‘The Effect of Metformin on Cardiac Fibrosis via Differentiation of Cardiac Fibroblasts'

“…They suggest that the inhibitory activity exerted by metformin on RAGE and HMBG1 [3] expression as well as inhibition of angiotensin-induced myofibroblast differentiation [4] may play a pivotal role in reducing postprocedural myocardial injury and improve the 1-year clinical outcomes.…”