| First Author | Bageghni SA | Year | 2018 |
| Journal | FASEB J | Volume | 32 |
| Issue | 9 | Pages | 4941-4954 |
| PubMed ID | 29601781 | Mgi Jnum | J:280512 |
| Mgi Id | MGI:6357085 | Doi | 10.1096/fj.201701455RR |
| Citation | Bageghni SA, et al. (2018) Cardiac fibroblast-specific p38alpha MAP kinase promotes cardiac hypertrophy via a putative paracrine interleukin-6 signaling mechanism. FASEB J 32(9):4941-4954 |
| abstractText | Recent studies suggest that cardiac fibroblast-specific p38alpha MAPK contributes to the development of cardiac hypertrophy, but the underlying mechanism is unknown. Our study used a novel fibroblast-specific, tamoxifen-inducible p38alpha knockout (KO) mouse line to characterize the role of fibroblast p38alpha in modulating cardiac hypertrophy, and we elucidated the mechanism. Myocardial injury was induced in tamoxifen-treated Cre-positive p38alpha KO mice or control littermates via chronic infusion of the beta-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 p38alpha 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 p38alpha activity. In conclusion, cardiac fibroblast p38alpha 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 p38alpha MAP kinase promotes cardiac hypertrophy via a putative paracrine interleukin-6 signaling mechanism. |
