AMPKa1 deletion in myofibroblasts exacerbates post myocardial infarction fibrosis by a miR-125b and Connexin 43 mechanism

Myofibroblasts (MFs) are crucial components of the fibrotic remodeling after myocardial infarction (MI). We have previously demonstrated the centrality of AMPKa1 in post-MI remodeling. Here, we investigate the effects of MF-specific deletion of AMPKa1 on left ventricular (LV) adaptation following MI, and the underlying molecular mechanisms. Importantly, MF-restricted AMPKa1 conditional knockout (cKO) hearts exhibit exacerbated post-MI adverse LV remodeling and are characterized by exaggerated fibrotic response, compared to wild-type (WT) hearts. Myofibroblast proliferation significantly increases in cKO infarcted hearts, coincident with a significant reduction of Connexin 43 (Cx43) expression in MFs. Mechanistically, lack of AMPKa1 in MFs enhances miR-125b expression, which, in turn, downregulates Cx43. Collectively, our data demonstrate a cardinal role for MF-AMPKa1 in cardiac remodeling, as its lineage-specific inactivation accentuates fibrosis and LV dilatation following MI. The deleterious effects of MF-specific AMPKa1 deletion are mediated via Cx43, and its post-transcriptional regulation by miR-125b. Overall design: We investigated the impact of AMPKa1 invalidation on mRNA profile in cultured human cardiac fibroblasts. We used 5 replicates per group,