中国病理生理杂志2025，Vol.41Issue(9)：1685-1693,9.DOI:10.3969/j.issn.1000-4718.2025.09.003
SMYD3介导的组蛋白H3K4me3修饰在大鼠PAH-ASD肺血管重构中的作用
Role of SMYD3-mediated histone H3K4me3 modification in pulmonary vascular remodeling in PAH-ASD rats
摘要
Abstract
AIM:To investigate the role of SET and MYND domain-containing protein 3(SMYD3)-mediated histone H3 lysine 4 trimethylation(H3K4me3)dysregulation in pulmonary vascular remodeling in a rat model of pulmo-nary arterial hypertension associated with atrial septal defect(PAH-ASD).METHODS:The PAH-ASD rat model was created using transseptal puncture and radiofrequency ablation techniques.The rats were randomly assigned to 5 groups:normal,sham,PAH-ASD,PAH-ASD+vehicle(Veh),and PAH-ASD+BCI-121(SMYD3 inhibitor).Four weeks after modeling,lung tissues and pulmonary vessels were harvested for subsequent analysis.Western blot analysis was conducted to evaluate the protein levels of SMYD3,H3K4me3,transforming growth faction-β1(TGF-β1),and collagen type Ⅲ(Col Ⅲ).The mRNA expression of TGF-β1 was quantified using RT-qPCR.Histological assessment of pulmonary vascu-lar fibrosis,vascular wall thickness and smooth muscle proliferation was executed through Masson's trichrome and HE staining.Co-immunoprecipitation(Co-IP)assay was performed to investigate the interactions among SMYD3,H3K4me3,and TGF-β1.Hemodynamic parameters,including mean pulmonary artery pressure(mPAP),were quantified using a computerized physiological signal acquisition system.RESULTS:The Western blot analysis indicated a significant in-crease in the protein levels of SMYD3,TGF-β1,Col Ⅲ,and H3K4me3 in the PAH-ASD group compared with the sham group(P<0.05).RT-qPCR corroborated the elevation of TGF-β1 mRNA expression in the PAH-ASD group(P<0.05).Furthermore,Masson's trichrome and HE staining techniques revealed more pronounced pulmonary vascular fibrosis,an augmented vascular wall area,and an elevated vascular area index within the PAH-ASD group(P<0.05).Additionally,the right ventricular hypertrophy index(RVHI)and mPAP were significantly elevated in the PAH-ASD group(P<0.05).The administration of BCI-121 resulted in a significant reduction of SMYD3,TGF-β1,Col Ⅲ,and H3K4me3 levels(P<0.05),while also mitigating pulmonary vascular fibrosis,RVHI,mPAP,pulmonary vascular area,and area index(P<0.05).Co-IP confirmed direct interactions among SMYD3,H3K4me3,and TGF-β1.CONCLUSION:Histone methyl-transferase SMYD3-mediated histone H3K4me3 modification plays a role in the pulmonary vascular remodeling of PAH-ASD model rats.The underlying mechanism may involve the regulation of pulmonary vascular proliferation and fibrosis me-diated by the overexpression of TGF-β1 and Col Ⅲ.关键词
动脉型肺动脉高压/房间隔缺损/SMYD3蛋白/组蛋白甲基化/肺血管重构Key words
pulmonary arterial hypertension/atrial septal defect/SMYD3 protein/histone methylation/pul-monary vascular remodeling分类
医药卫生引用本文复制引用
龙珊,吴书琪,彭昌,唐婷,陈连梅,王丽..SMYD3介导的组蛋白H3K4me3修饰在大鼠PAH-ASD肺血管重构中的作用[J].中国病理生理杂志,2025,41(9):1685-1693,9.基金项目
遵义市科技计划项目(遵市科合HZ字[2024]233号) （遵市科合HZ字[2024]233号）
