Study On The Role And Mechanism Of DCPIB In Myocardial Fibrosis

[Objective]:Cardiac fibrosis is the common pathological basis and therapeutic target of many cardiovascular diseases.Previous studies have shown that Volume Regulated Anion Channels(VRACs)could coutribute to organ fibrosis.DCPIB,a complex primarily known as 4-oxybutyric acid,has been extensively studied as a specific VRACs blocker,but its effect on cardiac fibrosis remains unclear.This study aims to investigate the inhibitory effect of DCPIB on the process of fibrosis after heart injury.[Methods]:In animal experiments,C57BL/6 mice was intraperitoneally injected with DCPIB(5mg/kg/day)for one week,and then TAC procedure was performed for establishing myocardial fibrosis.After the operation,mice were intraperitoneal administered DCPIB for 8 weeks.Echocardiography was used to assess cardiac function of mice in DCPIB administration group and sham group.After echocardiography,mice were sacrificed and heart tissue was obtained for detecting fibrosis related indicators so that can explore the effect of DCPIB on myocardial fibrosis after heart injury.In vitro,isolation of myocardial fibroblasts from rat and mice neonatal mice was performed for testing the role of mechanism of DCPIB in the differentiation,proliferation,migration and apoptosis of cardiac fibroblasts treated with TGFβ1 and ISO.[Results]:In animal experiments,the systolic function and left ventricular shortener fraction of mice treated with DCPIB(5mg/kg/day)were significantly improved,and the extent of myocardial fibrosis was significantly reduced compared with mice treated with TAC alone.In vitro,we found that DCPIB(10 μM)could not only inhibit the differentiation,migration,proliferation and collagen production of cardiac fibroblasts treated with TGFβ1 and ISO,but also antagonize the anti-apoptosis effect of TGFβ1 and ISO.At the mechanism level,DCPIB may plays an anti-fibrotic role in the development and progression of TAC-induced myocardial fibrosis by inhibiting SMAD2,P38,JNK,ERK and oxidative stress.[Conclusion]:DCPIB could improve TAC-induced myocardial fibrosis by inhibiting SMAD2,P38,JNK and ERK signaling proteins and oxidative stress,suggesting that DCPIB may be an potential candidate for treating myocardiacl fibrosis.