AMPKα1 deletion in myofibroblasts exacerbates post-myocardial infarction fibrosis by a connexin 43 mechanism

Abstract

We have previously demonstrated that systemic AMP-activated protein kinase α1 (AMPKα1) invalidation enhanced adverse LV remodelling by increasing fibroblast proliferation, while myodifferentiation and scar maturation were impaired. We thus hypothesised that fibroblastic AMPKα1 was a key signalling element in regulating fibrosis in the infarcted myocardium and an attractive target for therapeutic intervention. The present study investigates the effects of myofibroblast (MF)-specific deletion of AMPKα1 on left ventricular (LV) adaptation following myocardial infarction (MI), and the underlying molecular mechanisms. MF-restricted AMPKα1 conditional knockout (cKO) mice were subjected to permanent ligation of the left anterior descending coronary artery. cKO hearts exhibit exacerbated post-MI adverse LV remodelling and are characterised by exaggerated fibrotic response, compared to wild-type (WT) hearts. Cardiac fibroblast proliferation and MF content significantly increase in cKO infarcted hearts, coincident with a significant reduction of connexin 43 (Cx43) expression in MFs. Mechanistically, AMPKα1 influences Cx43 expression by both a transcriptional and a post-transcriptional mechanism involving miR-125b-5p. Collectively, our data demonstrate that MF-AMPKα1 functions as a master regulator of cardiac fibrosis and remodelling and might constitute a novel potential target for pharmacological anti-fibrotic applications.

Liquiritin Protects Against Cardiac Fibrosis After Myocardial Infarction by Inhibiting CCL5 Expression and the NF-κB Signaling Pathway

“… 7 The massive deposition of ECM and the decrease in the degradation of ECM lead to an imbalance and disturbance of the collagen structure, which eventually leads to MF. 11 The imbalance of MMP and excessive secretion of cytokines such as TGF-β eventually leads to MF. 54 , 55 It has been shown that the upregulation of MMPs after MI leads to a reduction in myocardial tissue thickness (thinning of the ventricular wall), which ultimately leads to deterioration of cardiac function.…”

Hypoxia-primed monocytes/macrophages enhance postinfarction myocardial repair

“…Studies have shown that AMPKα1 is a key molecule through which macrophages promote angiogenesis and tissue repair under normoxia and that the depletion of AMPKα1 impairs macrophage promotion of arteriogenesis 40 . AMPKα1 in fibroblasts was reported to function as a master regulator of cardiac fibrosis and remodeling after MI 41 . However, there have only been a few reports on the role of AMPKα2 in macrophages.…”

Apelin-13 Increases Functional Connexin-43 through Autophagy Inhibition via AKT/mTOR Pathway in the Non-Myocytic Cell Population of the Heart

“…Importantly, it has been reported that gap junction alteration in NMCs contributes to promoting arrhythmic events and adverse ventricular remodelling after myocardial infarction [ 11 ]. In addition, the downregulation of cardiac connexins can likewise trigger fibrosis [ 48 , 49 , 50 , 51 ]. Indeed, Cx43 downregulation and the consequent atrial gap junction interruption that characterise the atrial fibrillation condition are associated with an increase in fibrosis, which, in turn, further promotes conduction impairment and re-entry phenomenon development [ 25 ].…”