Research Paper Volume 13, Issue 22 pp 24580—24604

BMPR2 promoter methylation and its expression in valvular heart disease complicated with pulmonary artery hypertension

Ni Li1,2, *, , Linwen Zhu1, *, , Caimin Zhu1, , Hua Zhou1, , Dawei Zheng1, , Guodong Xu1, , Huoshun Shi1, , Jianqing Gao2, , Albert Jiarui Li3, , Zhaoyang Wang1, , Lebo Sun1, , Xiajun Li4, , Guofeng Shao1, ,

  • 1 Department of Cardiothoracic Surgery, Lihuili Hospital Affiliated to Ningbo University, Ningbo City, Zhejiang 315041, China
  • 2 Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
  • 3 Edgemont High School, Scarsdale, NY 10583, USA
  • 4 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
* Equal contribution

Received: September 4, 2021       Accepted: October 28, 2021       Published: November 18, 2021
How to Cite

Copyright: © 2021 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Valvular heart disease (VHD) is a common heart disease that affects blood flow. It usually requires heart surgery. Valvular heart disease complicated with pulmonary artery hypertension (VHD-PAH) may be lethal due to heart failure that results from increased heart burden. It is important for these patients to seek early treatment in order to minimize the heart damage. However, there is no reliable diagnosis method in VHD. In this study, we found DNA methylation was increased at the promoter of BMPR2 gene in the VHD patients compared with the healthy controls. This finding was confirmed by an independent cohort study of VHD patients and healthy controls. In addition, BMPR2 mRNA levels were reduced in the plasma of the VHD patients. There is strong correlation between BMPR2 promoter DNA methylation and the severity of VHD. Indeed, we found that both BMPR2 promoter DNA methylation and BMPR2 mRNA levels in the plasma are good biomarkers of VHD by themselves, with the respective AUC value of 0.879 and 0.725, respectively. When they were used in combination, the diagnostic value was even better, with the AUC value of 0.93. Consistent with the results in the VHD patients, we observed decreased BMPR2 and increased fibrosis in the lung of a PAH model mouse. BMPR2 was also decreased in the hearts of the PAH mice, whereas BMP4 was increased. Furthermore, BMPR2 was reduced in the heart valve tissue samples of human VHD patients after valve replacement with moderate/severe PAH compared with those with mild PAH. There was also increased apoptosis in the hearts of the PAH mice. BMPR2 promoter DNA methylation and its expression appear to be good biomarkers for VHD. Our results also suggest that DNA methylation may cause PAH through deregulation of BMP signaling and increased apoptosis.


BMPR2: bone morphogenetic protein receptor type 2; VHD: valvular heart disease; PASP: pulmonary artery systolic pressure; qRT-PCR: quantitative reverse transcription-polymerase chain reaction; ROC: receiver operating characteristic; BNP: brain natriuretic peptide; AUC: area under the ROC curve; MV: mitral valve; AV: aortic valve; TV: tricuspid valve; PV: pulmonary valve; PAH: pulmonary artery hypertension; HPH: high pulmonary arterial hypertension; IPH: idiopathic pulmonary arterial hypertension; MVR: mitral valve replacement; AVR: aortic valve replacement; DVR: double valve replacement; RVHD: rheumatic valvular heart disease; ECG: electrocardiography; TTE: transthoracic electrocardiography; TEE: transesophageal electrocardiography.