Introduction Cardiac fibroblasts represent the majority of non-myocyte cell population in the heart and play an essential role in cardiac remodelling. Following myocardial damage, cardiac fibroblasts can respond to damage-associated molecular patterns (DAMPs) and pro-inflammatory cytokines that stimulate specific intracellular signalling cascades, including p38 MAPK, to regulate cardiac fibroblast function. We aimed to understand the role of p38 MAPK signalling in the cardiac fibroblast during cardiac remodelling.
Methods A novel transgenic mouse model was developed to enable inducible and conditional knockout of p38α in fibroblasts in vivo using a Cre-loxP approach. Spatial and temporal deletion of p38α in fibroblasts was achieved by intra-peritoneal injection of tamoxifen. Adult tamoxifen-injected male mice (Cre-negative control and Cre-positive knockout) were subjected to myocardial injury by subcutaneous infusion of isoproterenol (ISO) or saline for 2 weeks, followed by removal of pumps and recovery for 1 week. Cardiac function was assessed by Millar conductance PV catheter. Heart samples were weighed and analysed by RT-PCR for mRNA and microRNA expression.
Results Isoproterenol infusion of control mice caused overt cardiac hypertrophy and dysfunction compared with saline-infused mice. This was indicated by deterioration of a number of cardiac parameters, including ejection fraction and end systolic volume, and up-regulation of cardiac hypertrophy markers (ANF, β-MHC) and hypertrophy-associated microRNAs. Fibroblast-specific p38α knockout mice exhibited remarkable protection against myocardial injury with improved cardiac function and normalisation of hypertrophy markers.
Conclusion p38α in cardiac fibroblasts plays a key role in driving cardiomyocyte hypertrophy and cardiac dysfunction and its deletion in fibroblasts is protective.
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