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.
Highlights
The p38 family of stress-activated MAPKs has an important role in cardiac signaling and is activated in both acute and chronic cardiac pathologies including myocardial
Our studies revealed that the effects of the cardiac damage-associated molecular pattern (DAMP) preparation on cardiac fibroblasts occurred independent of IL-1 receptor (IL-1R1) or TLR4 (Supplemental Fig. 2)
To determine whether fibroblast p38a was important for expression of the renin–angiotensin system (RAS) genes in fibroblasts and, thereby, potentially contributing to our in vivo findings by inhibiting local RAS activation, we investigated the effect of the p38 inhibitor SB203580 on RAS gene expression in cultured mouse cardiac fibroblasts (Supplemental Fig. 3A)
Summary
The p38 family of stress-activated MAPKs has an important role in cardiac signaling and is activated in both acute and chronic cardiac pathologies including myocardial. ABBREVIATIONS: Ang II, angiotensin II; DAMP, damage-associated molecular pattern; EF, ejection fraction; ESV, end systolic volume; Fb-p38a KO, fibroblast-specific p38a knockout; FGF2, fibroblast growth factor 2; IL-1R1, IL-1 receptor; ISO, isoproterenol; KO, knockout; LV, left ventricular; MACS, magnetic antibody cell separation; MHC, myosin heavy chain; miRNA, microRNA; PV, pressure–volume; RAS, renin–angiotensin system; WGA, wheat germ agglutinin. The expression and function of individual p38 subtypes varies in a cell- and tissuedependent manner; p38a is the most highly expressed subtype in the heart, with lower levels of p38g and p38d, and little or no expression of p38b [5, 6]. p38a knockout (KO) mice are not viable because of an essential role for this subtype in placental development [7]
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