2-Aminoethyl diphenylborinate inhibits bleomycin-induced skin and pulmonary fibrosis via interrupting intracellular Ca2+ regulation.

BACKGROUND

Systemic sclerosis (SSc) causes progressive fibrosis of multiple organs with the low efficacy of immunosuppressive therapies. Our previous study indicated the SSc pathological pathways are closely correlated with Ca2+ signals, and blockage of the intracellular Ca2+ elevation facilitates inhibition of SSc pathogenesis.

OBJECTIVE

Transforming growth factor β (TGF-β)-modulated SMAD signaling is crucial in regulating SSc pathogenesis. Whether Ca2+ signals are involved in TGF-β1/SMAD signaling-induced fibrotic process has been further investigated.

METHODS

We utilized TGF-β1-induced myofibroblasts as a model to detect how Ca2+ signals affected SSc pathogenesis, and investigated the combination of treatment with store-operated Ca2+ entry (SOCE) associated inhibitors, 2-aminoethyl diphenylborinate (2-APB) and SKF96365 to restrain the increased Ca2+ signaling in myofibroblasts. In addition, the SSc bleomycin mouse model was used to detect the effect of 2-APB on SSc pathogenesis in vivo.

RESULTS

Our findings revealed increased levels of TGF-β1 production in SSc was associated with intracellular Ca2+ activity, and inhibition of intracellular Ca2+ regulation by 2-APB resulted in the dedifferentiation of TGF-β1-induced myofibroblasts. This was due to the fact that 2-APB restrained the expression fibrotic markers, α-SMA, fibronectin and vimentin through inhibiting TGF-β1/SMAD3 signaling. Thus, subcutaneous injection of 2-APB improved bleomycin-induced skin and pulmonary fibrosis.

CONCLUSION

2-APB is a potential candidate for treating fibrosis, by disrupting intracellular Ca2+ regulation in SSc to induce the dedifferentiation of myofibroblasts and meliorates fibrosis pathogenesis via inhibiting TGF-β1/SMAD3 signaling.