Arecoline Enhances Phosphodiesterase 4A Activity to Promote Transforming Growth Factor-β-Induced Buccal Mucosal Fibroblast Activation via cAMP-Epac1 Signaling Pathway

被引：16

作者：

Zhang, Bo ^{[1
]}

Gao, Lihua ^{[2
]}

Shao, Chunsheng ^{[1
]}

Deng, Mingsi ^{[3
]}

Chen, Liangjian ^{[1
]}

机构：

[1] Cent South Univ, Xiangya Hosp 3, Dept Stomatol, Changsha, Peoples R China

[2] Cent South Univ, Xiangya Hosp 3, Dept Dermatol, Changsha, Peoples R China

[3] Changsha Stomatol Hosp, Dept Orthodont, Changsha, Peoples R China

来源：

FRONTIERS IN PHARMACOLOGY | 2021年 / 12卷

关键词：

oral submucous fibrosis; buccal mucosal fibroblast; arecoline; PDE4A; cAMP-Epac1 signaling pathway; ORAL SUBMUCOUS FIBROSIS; POSSIBLE PATHOGENESIS; GENE-EXPRESSION; UP-REGULATION; KINASE; MECHANISMS; INHIBITOR; SMOKING; SAFROLE; CELLS;

D O I：

10.3389/fphar.2021.722040

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Chewing areca nut (betel quid) is strongly associated with oral submucous fibrosis (OSF), a pre-cancerous lesion. Among the areca alkaloids, arecoline is the main agent responsible for fibroblast proliferation; however, the specific molecular mechanism of arecoline affecting the OSF remains unclear. The present study revealed that arecoline treatment significantly enhanced Transforming growth factor-beta (TGF-beta)-induced buccal mucosal fibroblast (BMF) activation and fibrotic changes. Arecoline interacts with phosphodiesterase 4A (PDE4A) to exert its effects through modulating PDE4A activity but not PDE4A expression. PDE4A silence reversed the effects of arecoline on TGF-beta-induced BMFs activation and fibrotic changes. Moreover, the exchange protein directly activated by cAMP 1 (Epac1)-selective Cyclic adenosine 3 ',5 '-monophosphate (cAMP) analog (8-Me-cAMP) but not the protein kinase A (PKA)-selective cAMP analog (N6-cAMP) remarkably suppressed alpha-smooth muscle actin(alpha-SMA) and Collagen Type I Alpha 1 Chain (Col1A1) protein levels in response to TGF-beta 1 and arecoline co-treatment, indicating that cAMP-Epac1 but not cAMP-PKA signaling is involved in arecoline functions on TGF-beta 1-induced BMFs activation. In conclusion, arecoline promotes TGF-beta 1-induced BMFs activation through enhancing PDE4A activity and the cAMP-Epac1 signaling pathway during OSF. This novel mechanism might provide more powerful strategies for OSF treatment, requiring further in vivo and clinical investigation.

引用

页数：12

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