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Our previous study found that tryptase activated atrial fibroblasts, increased collagen synthesis in atrial fibroblasts through protease activated receptor-2 (PAR2) receptors. Recent studies showed that cytoskeleton-associated protein 4 (CKAP4) played an important role in ventricular fibroblast activation. The present study aimed to investigate the role of CKAP4 in tryptase-induced atrial fibroblast activation, atrial fibrosis, and molecular regulatory mechanisms. We cultured atrial fibroblasts in vitro, gave cells tryptase stimulation, then overexpressed or silenced PAR2 and CKAP4 genes in the cells. Their effects on atrial fibroblast proliferation, migration, extracellular matrix remodeling (Collagen I and fibronectin) and downstream key molecules (TGF-β1, c-jun and c-fos, JNK, p38) were investigated. The results showed that the expression of CKAP4 was significantly increased by tryptase and further increased by pcDNA3.1-PAR2, but decreased by FALLRY-NH2 and PAR2 siRNA. CKAP4 overexpression significantly increased the cell proliferation, migration and levels of Collagen I and fibronectin, matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinases-1 (TIMP-1) levels in atrial fibroblasts, while CKAP4 siRNA significantly reduced them. CKAP4 overexpression significantly increased the expression of TGF-β1, c-jun and c-fos, and activated the JNK/p38 pathway, which were suppressed by CKAP4 siRNA. In conclusion, CKAP4 is involved in tryptase-induced phenotypic conversion in atrial fibroblasts through PAR2/p38/JNK pathway, which may provide novel targets in the prevention of atrial fibrosis. AJTR Copyright © 2021.

Citation

Hongwei Tan, Zhisong Chen, Fei Chen, Wenjun Xu, Xuebo Liu. CKAP4 participates in tryptase-induced phenotypic conversion in atrial fibroblasts through PAR2/p38/JNK pathway. American journal of translational research. 2021;13(4):2270-2282


PMID: 34017388

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