Rationale:

Our recent work unmasked an unexpected link between inflammation and adverse cardiac remodeling via activation of the transcription factor myocyte enhancer factor 2 (MEF2). We identified a signaling pathway consisting of PGE2, EP3-receptors, PKD and Rac1 leading to a nucleo-cytoplasmic shuttling of HDAC5 with subsequent activation of MEF2. Here, we aimed to elucidate the in vivo role of  MEF2 in a model of acute inflammatory cardiomyopathy. 

Results:

Exposure of BALB/c-mice to 7 mg/kg from E. coli derived lipopolysaccharide (LPS) led to severe depression of left-ventricular function and was accompanied by considerably increased levels of PGE2. Strikingly, cardiac myocyte-specific MEF2D deficient mice (MEF2D-KO) were largely protected from LPS-induced acute heart failure, as documented by preserved ejection fraction (LVEF after 24 hours: 49% in contrast to 31% in LPS-treated littermates) and prolonged survival (48 hours after induction: 43% of MEF2D-KO vs. 0% of littermates) in LPS-endotoxemia. Moreover, expression of typical target genes of MEF2 (e.g. Myomaxin) were attenuated in MEF2D-KO, confirming that the loss of MEF2D contributed to reduced MEF2 activity. A cardiomyocyte-specific unbiased transcriptome-sequencing in the early stage of inflammation-induced acute heart failure revealed new MEF2D-dependent genes. 

Conclusion: