Department of Cardiothoracic Surgery, Lihuili Hospital Affiliated to Ningbo University, Ningbo City, Zhejiang 315041, China.
Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Aging (Albany NY). 2021 Nov 18;13(22):24580-24604. doi: 10.18632/aging.203690.
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 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, mRNA levels were reduced in the plasma of the VHD patients. There is strong correlation between promoter DNA methylation and the severity of VHD. Indeed, we found that both promoter DNA methylation and 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. 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.
心脏瓣膜病（VHD）是一种常见的影响血流的心脏病，通常需要心脏手术。由于心脏负荷增加导致心力衰竭，心脏瓣膜病合并肺动脉高压（VHD-PAH）可能是致命的。这些患者寻求早期治疗以尽量减少心脏损伤非常重要。然而，VHD 没有可靠的诊断方法。在这项研究中，我们发现与健康对照组相比，VHD 患者基因启动子的 DNA 甲基化增加。这一发现得到了 VHD 患者和健康对照组的独立队列研究的证实。此外，VHD 患者血浆中的 mRNA 水平降低。基因启动子 DNA 甲基化与 VHD 的严重程度之间存在很强的相关性。事实上，我们发现基因启动子 DNA 甲基化和血浆中的 mRNA 水平本身就是 VHD 的良好生物标志物，其 AUC 值分别为 0.879 和 0.725。当它们联合使用时，诊断价值甚至更好，AUC 值为 0.93。与 VHD 患者的结果一致，我们观察到肺动脉高压模型小鼠的肺中 BMPR2 减少和纤维化增加。PAH 小鼠的心脏中 BMPR2 也减少，而 BMP4 增加。此外，与轻度 PAH 相比，中度/重度 PAH 患者在瓣膜置换后心脏瓣膜组织样本中 BMPR2 减少。PAH 小鼠的心脏中也有更多的细胞凋亡。基因启动子 DNA 甲基化及其表达似乎是 VHD 的良好生物标志物。我们的结果还表明，DNA 甲基化可能通过 BMP 信号通路的失调和细胞凋亡的增加导致 PAH。
