期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 18, 页码 -出版社
MDPI
DOI: 10.3390/ijms221810072
关键词
cardiac fibroblasts; WNT3a; WNT5a; beta-catenin; TGF-beta signaling; IL-11; cardiac fibrosis
资金
- National Science Centre (Poland) [2014/14/E/NZ5/00175]
The study revealed that WNT/beta-catenin signaling promotes the transition of cardiac fibroblasts to myofibroblasts by enhancing IL-11 production in TGF-beta-mediated pathways, while non-canonical WNT5a co-activation suppressed TGF-beta-induced collagen I production.
Cardiac fibrosis is a pathological process associated with the development of heart failure. TGF-beta and WNT signaling have been implicated in pathogenesis of cardiac fibrosis, however, little is known about molecular cross-talk between these two pathways. The aim of this study was to examine the effect of exogenous canonical WNT3a and non-canonical WNT5a in TGF-beta-activated human cardiac fibroblasts. We found that WNT3a and TGF-beta induced a beta-catenin-dependent response, whereas WNT5a prompted AP-1 activity. TGF-beta triggered profibrotic signatures in cardiac fibroblasts, and co-stimulation with WNT3a or co-activation of the beta-catenin pathway with the GSK3 beta inhibitor CHIR99021 enhanced collagen I and fibronectin production and development of active contractile stress fibers. In the absence of TGF-beta, neither WNT3a nor CHIR99021 exerted profibrotic responses. On a molecular level, in TGF-beta-activated fibroblasts, WNT3a enhanced phosphorylation of TAK1 and production and secretion of IL-11 but showed no effect on the Smad pathway. Neutralization of IL-11 activity with the blocking anti-IL-11 antibody effectively reduced the profibrotic response of cardiac fibroblasts activated with TGF-beta and WNT3a. In contrast to canonical WNT3a, co-activation with non-canonical WNT5a suppressed TGF-beta-induced production of collagen I. In conclusion, WNT/beta-catenin signaling promotes TGF-beta-mediated fibroblast-to-myofibroblast transition by enhancing IL-11 production. Thus, the uncovered mechanism broadens our knowledge on a molecular basis of cardiac fibrogenesis and defines novel therapeutic targets for fibrotic heart diseases.
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