| Objective To study the effect of the transcription factor O subfamily 1(Fox O1)on autophagy of pulmonary artery in chronic thromboembolic pulmonary hypertension(CTEPH)rats.Methods Rats were divided into normal control group and three experimental groups.Three experimental groups were simple thrombosis group,Fox O1 agonist treatment group and Fox O1 inhibitor treatment grouprespectively.In the experimental group,autologous thrombosis was injected into the pulmonary artery from the left external carotid artery to induce the CTEPH animal model.The normal control group was treated with the same amount of saline instead of autologous blood clot.Each group was divided into three subgroups that two weeks,four weeks and eight weeks.Fox O1 agonist treatment group was treated with restrovesol(Res)10mg/kg/d for two weeks,Fox O1 inhibitor treatment group was treated with AS1842856 30mg/kg in two weeks.The thrombus group was given the same amount of normal saline.After 2 week,4 week and 8 week,detected mean pulmonary arterial pressure(m PAP).Isolated pulmonary artery,histopathology and vessel wall area/total area(WA/TA)were measured.The expression of Fox O1,p Fox O1,LC3 and Beclin1 antigen were detected by immune histochemistry and the expression of Fox O1 m RNA,LC3 m RNA and Beclin1 m RNA in the pulmonary arteries were determined by RT-PCR.The expression of Fox O1,p Fox O1,LC3,Beclin1 proteinwere determined by western blot,then compared and analyzed the correlation.Results The m PAP and WA/TA ratio in thrombus group and the inhibitor group were higher than the normal control group(P<0.05).The m PAP and WA/TA ratio in the inhibitor group was higher than the corresponding thrombus group,and the difference was statistically significant(P<0.05).But there was no significant difference in m PAP in 8w group(P>0.05).The m PAP and WA/TA ratio in agonist group increased with the prolongation of time,but the increase rate was lower,which was lower than thrombus group and higher than the normal control group.There was no significant difference in the expression of Fox O1 m RNA,LC3 m RNA and Beclin1 m RNA in normal control group.The expression of Fox O1 m RNA,LC3 m RNA and Beclin1 m RNA in thrombosis group and inhibitor group were significantly lower than the normal control group(P<0.05).The expression of Fox O1 m RNA,LC3 m RNA and Beclin1 m RNA in agonist group increased with time,but lower than normal control group,the difference was statistically significant at two weeks and four weeks(P<0.05),but not statistically significant in eight weeks.The expression of Fox O1,p Fox O1,LC3 and Beclin1 protein in the thrombus group and inhibitor group decreased with time and were significantly lower than the normal control group,the difference was statistically significant(P<0.05).The expression of Fox O1,p Fox O1,LC3 and Beclin1 protein in the agonist group increased with timeand higher than the thrombus group and inhibitor group,the difference was statistically significant(P<0.05),but lower than the normal control(P<0.05).There was significant difference intwo weeks and four weeks group(P<0.05)but no significant difference in eight weeks.The expression of p Fox O1 protein was negatively correlated with m PAP(r=-0.967,P<0.05),and positively correlated with Fox O1(r=0.972,P<0.05),LC3(r=0.871,P<0.05),Beclin1(r=0.953,P<0.05)protein.Conclusion Autophagy in pulmonary arterial of CTEPH rats decreased.Res,a Fox O1 agonist,could decrease the pulmonary artery pressure in CTEPH rats,enhance autophagy in pulmonary artery and improve the pulmonary arterial remodeling of pulmonary arteries in CTEPH rats.AS1842856 a Fox O1 inhibitor,could increase the pulmonary arterial pressure in CTEPH rats,reduce autophagy in pulmonary artery and enhance pulmonary artery endothelial remodelingin CTEPH rats,suggesting that Fox O1 may be involved in the process of endothelial remodelingin CTEPH,and related to the development of CTEPH. |
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