Cardiac fibroblast‐specific p38α MAP kinase promotes cardiac hypertrophy via a putative paracrine interleukin‐6 signaling mechanism

Abstract

Recent studies suggest that cardiac fibroblast-specific p38α MAPK contributes to the development of cardiac hypertrophy, but the underlying mechanism is unknown. Our study used a novel fibroblast-specific, tamoxifen-inducible p38α knockout (KO) mouse line to characterize the role of fibroblast p38α in modulating cardiac hypertrophy, and we elucidated the mechanism. Myocardial injury was induced in tamoxifen-treated Cre-positive p38α KO mice or control littermates via chronic infusion of the β-adrenergic receptor agonist isoproterenol. Cardiac function was assessed by pressure-volume conductance catheter analysis and was evaluated for cardiac hypertrophy at tissue, cellular, and molecular levels. Isoproterenol infusion in control mice promoted overt cardiac hypertrophy and dysfunction (reduced ejection fraction, increased end systolic volume, increased cardiac weight index, increased cardiomyocyte area, increased fibrosis, and up-regulation of myocyte fetal genes and hypertrophy-associated microRNAs). Fibroblast-specific p38α KO mice exhibited marked protection against myocardial injury, with isoproterenol-induced alterations in cardiac function, histology, and molecular markers all being attenuated. In vitro mechanistic studies determined that cardiac fibroblasts responded to damaged myocardium by secreting several paracrine factors known to induce cardiomyocyte hypertrophy, including IL-6, whose secretion was dependent upon p38α activity. In conclusion, cardiac fibroblast p38α contributes to cardiomyocyte hypertrophy and cardiac dysfunction, potentially via a mechanism involving paracrine fibroblast-to-myocyte IL-6 signaling.-Bageghni, S. A., Hemmings, K. E., Zava, N., Denton, C. P., Porter, K. E., Ainscough, J. F. X., Drinkhill, M. J., Turner, N. A. Cardiac fibroblast-specific p38α MAP kinase promotes cardiac hypertrophy via a putative paracrine interleukin-6 signaling mechanism.

Three in a Box: Understanding Cardiomyocyte, Fibroblast, and Innate Immune Cell Interactions to Orchestrate Cardiac Repair Processes

“…Vice versa, in hypertrophic cardiomyopathy, mutations in sarcomeric proteins in cardiomyocytes can lead to increased profibrotic gene expression and proliferation of non-myocytes (170). This vicious cell interaction circle was recently confirmed by demonstrating that activation of p38α in adult cardiac fibroblasts, under β-adrenergic receptor stimulation, leads to IL-6 secretion that paracrinely causes cardiomyocyte hypertrophy (171). On the other hand, stimulation of protein kinase A in cardiomyocytes leads to CTGF and VEGF secretion that paracrinely induce collagen production and fibroblast proliferation leading to fibrosis (172).…”

Overexpression of miR‐199/214 is a distinctive feature of iron‐induced and asbestos‐induced sarcomatoid mesothelioma in rats

“…The overexpression of miR‐214 suppressed the phosphorylation of p38 in bone marrow‐derived mesenchymal stem cells, 51 while it increased the cellular proliferation and phosphorylation of ERK induced by isoproterenol (β‐adrenergic receptor agonist) in cardiac fibroblast 52 . Furthermore, the absence of p38α MAP kinase, which was phosphorylated by isoproterenol, in cardiac fibroblast suppressed the isoproterenol‐induced elevation of miR‐214 53 . The functional role of miR‐199/214 in oxidative stress warrants further investigation.…”

Transforming growth factor–β in tissue fibrosis

“…Both in vitro and in vivo findings have suggested that p38 MAPK may play a role in the pathogenesis of renal fibrosis, acting downstream of TGF-β (Stambe et al, 2004). In models of cardiac injury, fibroblast-specific loss of p38 MAPK attenuated fibrotic and hypertrophic remodeling (Molkentin et al, 2017;Bageghni et al, 2018). Other studies have suggested that the MAPK kinase kinase (MAPKKK) TGF-activated kinase (TAK1) stimulates a matrix-synthetic fibroblast phenotype in vitro (Ono et al, 2003) and in vivo (Guo et al, 2013), presumably acting upstream of MAPKs.…”