β3-AR/β-arrestin2 Interaction Triggers Cardiac Fibrosis Through JNK/c-Jun Pathway in Cardiac Fibroblasts.
Z, X., M, Z., C, Z., J, D., J, D., J, L., X, Y., J, W., Y, D., & W, W. (2026). β3-AR/β-arrestin2 Interaction Triggers Cardiac Fibrosis Through JNK/c-Jun Pathway in Cardiac Fibroblasts.. Journal of cellular and molecular medicine. https://doi.org/10.1111/jcmm.71305
Z X, M Z, C Z, J D, J D, J L, et al. β3-AR/β-arrestin2 Interaction Triggers Cardiac Fibrosis Through JNK/c-Jun Pathway in Cardiac Fibroblasts.. Journal of cellular and molecular medicine. 2026; doi: 10.1111/jcmm.71305
Z X, M Z, C Z, et al. β3-AR/β-arrestin2 Interaction Triggers Cardiac Fibrosis Through JNK/c-Jun Pathway in Cardiac Fibroblasts.[J]. Journal of cellular and molecular medicine. 2026. DOI: 10.1111/jcmm.71305.
@article{z2026,
author = {Xu Z and Zhu M and Zhou C and Duan J and Ding J and Liu J and Ying X and Wu J and Dong Y and Wang W},
title = {β3-AR/β-arrestin2 Interaction Triggers Cardiac Fibrosis Through JNK/c-Jun Pathway in Cardiac Fibroblasts.},
journal = {Journal of cellular and molecular medicine},
year = {2026},
doi = {10.1111/jcmm.71305},
note = {PMID: 42547946},
}
TY - JOUR AU - Xu Z AU - Zhu M AU - Zhou C AU - Duan J AU - Ding J AU - Liu J AU - Ying X AU - Wu J AU - Dong Y AU - Wang W TI - β3-AR/β-arrestin2 Interaction Triggers Cardiac Fibrosis Through JNK/c-Jun Pathway in Cardiac Fibroblasts. T2 - Journal of cellular and molecular medicine PY - 2026 DO - 10.1111/jcmm.71305 AN - PMID:42547946 ER -
Myocardial fibrosis (MF) is a critical pathological substrate of heart failure (HF), and β3-adrenergic receptor (β3-AR) has been implicated in cardiac remodelling with controversial roles. This study aimed to clarify the pro-fibrotic mechanism of β3-AR in cardiac fibroblasts and its association with β-arrestin2-mediated biased activation. Primary cardiac fibroblasts were isolated from neonatal C57BL/6 mice and subjected to β3-AR overexpression, agonist (BRL37344) stimulation, antagonist (SR59230A) inhibition, JNK inhibitor (SP600125) treatment, or β-arrestin2 knockdown via siRNA. RNA sequencing, immunofluorescence, Western blotting, and coimmunoprecipitation assays were performed to explore molecular mechanisms. RNA sequencing identified 577 upregulated and 231 downregulated genes in β3-AR-activated fibroblasts, enriched in extracellular matrix organisation and inflammatory pathways. Functional experiments confirmed that BRL37344 significantly upregulated fibrosis markers (α-SMA, FN, collagen I/III) and TGF-β1 expression, which was reversed by SP600125. Notably, inhibition of Gi signalling by pertussis toxin (PTX) failed to block β3-AR-induced fibrosis, while β-arrestin2 knockdown abrogated JNK/c-Jun/TGF-β1 pathway activation. Immunofluorescence and coimmunoprecipitation verified colocalisation and direct interaction between β3-AR and β-arrestin2, which was enhanced by BRL37344. Our findings demonstrate that β3-AR promotes cardiac fibrosis through β-arrestin2-mediated biased activation of the JNK/c-Jun/TGF-β1 pathway, independent of classical Gi signalling. This study reveals a novel cell-specific signalling mechanism of β3-AR and provides a potential therapeutic target for developing precision drugs against MF and HF.