The Mechanism Of TG2 Inhibitor In Alleviating Pulmonary Vascular Remodeling In Rats With Pulmonary Artery Hypertension

Objective: To investigate the mechanism of TG2 inhibitor in alleviating pulmonary vascular remodeling in rats with pulmonary artery hypertension.Methods: 1.The animal model of pulmonary artery hypertension(PAH)was established by rats with there left lung removed and monocrotaline(MCT)injected.Cystamine dihydrochloride,as transglutaminase 2(TG2)inhibitor,was used to intervene on the formation of pulmonary vascular remodeling in PAH.2.30 healthy male Sprague-Dawley rats were randomly divided into 3 groups: control group(n=10,without any treatment,feeding in the same environment as other two groups);model group(n=10),received the left lung resection plus MCT injection(60mg/kg)on the 7th day after left pneumonectomy;intervention group(n=10),rats treated with cystamine dihydrochloride(112mg/kg,once daily)on the 5th day after left pneumonectomy.3.All rats were executed on the 35 th day after pneumonectomy,and then detecting the mean pulmonary arterial pressure(m PAP)of each group,then calculating the right ventricle hypertrophy index.4.The methods of pulmonary elastic fiber dyeing,lung tissue HE staining were used to observe the pulmonary blood vessels and the lung tissue pathological change,medial hypertrophy of small pulmonary arteries(WT%),vessel wall area to total area ratio(WA%)and the neointimal proliferationdegree.5.Expression of Akt m RNA of the lung tissues in rats was detected by RT-PCR.6.The protein expression of Akt and P-Akt were examined by Western blot.Results: 1.The rats received the left lung resection and MCT injection developed severe pulmonary hypertension,right ventricular hypertrophy and intimal formation.m PAP,RVHI%,WT%,WA% and the percentage of neointimal hyperplasia were significantly increased compared with the control group.The differences were statically significant(p<0.05).2.After treatment of cystamine dihydrochloride,m PAP,RVHI%,WT%,WA% and the percentage of neointimal hyperplasia decreased with statically significant(p<0.05).3.The m RNA level of Akt in the lung tissues of rats with PAH up-regulated significantly by RT-PCR,compared with control(p<0.05),and the protein expression of Akt and p-Akt also increased significantly by Western blot,compared with the control group(p<0.05).The m RNA level of Akt and the protein expression of Akt and p-Akt decreased significantly in the lung tissues of rats treated with cystamine dihydrochloride,compared with the model group(p<0.05).Conclusion:1.The rats with PAH were successfully induced by left pneumonectomy plus monocrotaline injection,with the formation of neointimal hyperplasia and typical pathological features of pulmonary vascular remodeling of obstructive pulmonary hypertension.2.TG2 inhibitor may prevent the formation of PAH and pulmonary vascular remodeling to a certain extent.3.The PI3K/Akt signaling pathway may play a important role in pulmonary vascular remodeling in rats with PAH whichinhibited by TG2 inhibitor.