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

ABSTRACT: 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.

SUBMITTER: Li N

PROVIDER: S-EPMC8660616 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundEpigenetic mechanisms are critical in the pathogenesis of pulmonary arterial hypertension (PAH). Previous studies have suggested that hypermethylation of the BMPR2 (bone morphogenetic protein receptor type 2) promoter is associated with BMPR2 downregulation and progression of PAH. Here, we investigated for the first time the role of SIN3a (switch-independent 3a), a transcriptional regulator, in the epigenetic mechanisms underlying hypermethylation of BMPR2 in the pathogenesis of PAH.MethodsWe used lung samples from PAH patients and non-PAH controls, preclinical mouse and rat PAH models, and human pulmonary arterial smooth muscle cells. Expression of SIN3a was modulated using a lentiviral vector or a siRNA in vitro and a specific adeno-associated virus serotype 1 or a lentivirus encoding for human SIN3a in vivo.ResultsSIN3a is a known transcriptional regulator; however, its role in cardiovascular diseases, especially PAH, is unknown. It is interesting that we detected a dysregulation of SIN3 expression in patients and in rodent models, which is strongly associated with decreased BMPR2 expression. SIN3a is known to regulate epigenetic changes. Therefore, we tested its role in the regulation of BMPR2 and found that BMPR2 is regulated by SIN3a. It is interesting that SIN3a overexpression inhibited human pulmonary arterial smooth muscle cells proliferation and upregulated BMPR2 expression by preventing the methylation of the BMPR2 promoter region. RNA-sequencing analysis suggested that SIN3a downregulated the expression of DNA and histone methyltransferases such as DNMT1 (DNA methyltransferase 1) and EZH2 (enhancer of zeste 2 polycomb repressive complex 2) while promoting the expression of the DNA demethylase TET1 (ten-eleven translocation methylcytosine dioxygenase 1). Mechanistically, SIN3a promoted BMPR2 expression by decreasing CTCF (CCCTC-binding factor) binding to the BMPR2 promoter. Last, we identified intratracheal delivery of adeno-associated virus serotype human SIN3a to be a beneficial therapeutic approach in PAH by attenuating pulmonary vascular and right ventricle remodeling, decreasing right ventricle systolic pressure and mean pulmonary arterial pressure, and restoring BMPR2 expression in rodent models of PAH.ConclusionsAll together, our study unveiled the protective and beneficial role of SIN3a in pulmonary hypertension. We also identified a novel and distinct molecular mechanism by which SIN3a regulates BMPR2 in human pulmonary arterial smooth muscle cells. Our study also identified lung-targeted SIN3a gene therapy using adeno-associated virus serotype 1 as a new promising therapeutic strategy for treating patients with PAH.

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

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