Genetic Characteristics And Pathogenic Mechanisms Of BMP-BMPR2 Signaling Pathway Mutations In Pulmonary Arterial Hypertensio

Background:Currently,we have more than two dozen known causative genes for pulmonary arterial hypertension,which together can explain the etiology of 50%-80%of hereditary PAH and 20%-50%of IPAH patients.Methods:From March 2021 to October 2021,we received 18 patients with idiopathic and familial pulmonary hypertension in the "genetic Clinic of pulmonary vascular Disease" of Fuwai Hospital.Whole-enome sequencing was used to detect mutation,and the effect on protein function was predicted with Polyphen2 and SIFT.We classified and evaluated the mutation types by ACMG score.Results:Eleven Of the eighteen patients had mutations,with a mutation rate of 61.1%.The mutation detection rates were 53.3%(8/15)and 100%(3/3)in IPAH patients and FPAH patients.We found 8 BMPR2 mutations,1 BMP9 mutation,1 PTGIS mutation,1 EIF2AK4 mutation,1 SOX17 mutation and 1 AQP1 mutation,of which 61.5%were new mutations.One patient with IPAH and one patient with FPAH carried double mutations of EIF2AK4 and BMPR2,SOX17 and AQP1.The two patients tended to have early-onset and a severe clinical phenotype.Conclusion:Bmp-bmpr2 signaling pathway is the main pathogenic gene of pulmonary hypertension,accounting for 77%.The ’double hit’ caused by double mutant gene may be the key mechanism of pulmonary hypertension.Background:Genetic evidence implicates bone morphogenetic protein 9(BMP9)as a culprit gene for pulmonary arterial hypertension(PAH)and loss of BMP9 signaling increases the susceptibility to PAH.However,experimental animal studies demonstrate that deletion or inhibition of BMP9 prevents or even reverses pulmonary vascular remodeling.To address this contradictory,we generated a BMP9 transgenic rat model(Tg-BMP9)and analyzed the long-term effect of BMP9 on the pulmonary vascular.Methods:We generated transgenic SD rat lines with overexpression of human BMP9 specifically in the liver using the ALB promoter.The phenotype characteristics of pulmonary artery were analyzed at baseline or exposed to of monocrotaline stimulation(60 mg/kg)for 3 weeks.Results:Tg-BMP9 rats were normal at 2 months of age.Monocrotaline induced pulmonary hypertension and right ventricular hypertrophy in the wild-type littermates.However,these pathological remodeling were almost completely prevented by BMP9 overexpressing.Compared to the wild-type littermates,the diastolic right ventricular wall thickness(RVAW;d)and diastolic right ventricular internal diameter(RVID;d)were reduced by 33%and 45%in Tg-BMP9 rats,respectively.Right heart catheter assessment demonstrated mean pulmonary arterial pressure(mPAP)were decreased to 20 mmHg in Tg-BMP9 rats.Histological analyses revealed that the wall thickness of small pulmonary arteries were less in Tg-BMP9 rats than in wild-type littermates.Conclusion:Overexpression of BMP9 does not cause spontaneous PAH at 2 months of age.In contrast,it prevents monocrotaline-induced pulmonary remodeling.These results demonstrate overexpression of BMP9 could be a promising therapeutic strategy for PAH.Objective:Congenital heart disease combined with pulmonary hypertension is the most common type of pulmonary hypertension in China.The disease burden is heavy,but the pathological mechanism is still unclear.Therefore,there is an urgent need for an animal model close to the phenotype of clinical patients.We constructed the rat models of congenital heart disease(CHD)and congenital heart disease combined with pulmonary hypertension(CHD-PAH),and compared the trend of cardiac remodeling under two different conditions.Methods:One group of rats were subjected to shunt(n=5)and another group used shunt+MCT(n=8)to induced CHD and CHD-PAH.We performed echocardiography every week.The rats in the shunt group were observed for 8 weeks and the rats in the shunt+MCT group were observed for 3 weeks.Results:The cardiac remodeling of rats in shunt group was mainly left heart.The left ventriclar anterior wall thickened 19%(p=0.02),the internal diameter increased 36%(p=0.0004)at 1 weeks after operation.Two weeks after operation,the internal diameter of right ventricle in this group increased(p=0.001).At 3 weeks after operation,the right ventriclar anterior wall reached statistical difference(p=0.03).The left and right heart reached a new balance at 6 weeks after operation.In the shunt+MCT group,the left ventricular internal diameter increased by 13%(p=0.001),but the right ventricular remodeling was more significant:the right ventricular anterior wall thickened by 24%(p=0.01),the right ventricular diameter increased by 28%(p=0.02),and the right ventricular outflow tract widened by 29%(p<0.0001).The severely remodeling right heart brought more pressure to the left heart,and the left and right heart was unbalanced at 3 weeks after operation.Conclusions:Compared with shunt,shunt+MCT double hit caused strong and rapid right ventricular remodeling,which simulated the cardiac remodeling phenotype of patients with CHD-PAH,and been a great significance to the future mechanism research.