1. DNA methyltransferase 3B deficiency unveils a new pathological mechanism of pulmonary hypertension
- Author
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Xin Jiang, Yi Yan, Jiwang Chen, Shan-Shan Guo, Shuyang Zhang, Xi-Qi Xu, Su-Qi Li, Yang-Yang He, Zhi-Cheng Jing, Ru-Jiao Zhang, Jue Ye, Dan Lu, Xue Zhang, Tian-Yu Lian, Kai Sun, Yong Wang, Jun-Han Zhao, Xu Zhang, and Lian-Feng Zhang
- Subjects
Hypertension, Pulmonary ,DNMT3B ,Becaplermin ,Diseases and Disorders ,030204 cardiovascular system & hematology ,Vascular Remodeling ,Pathogenesis ,Rats, Sprague-Dawley ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Mediator ,Right ventricular hypertrophy ,medicine.artery ,medicine ,Animals ,Humans ,Epigenetics ,Health and Medicine ,DNA (Cytosine-5-)-Methyltransferases ,Hypoxia ,Research Articles ,Cells, Cultured ,030304 developmental biology ,Cell Proliferation ,0303 health sciences ,Multidisciplinary ,business.industry ,SciAdv r-articles ,medicine.disease ,Pulmonary hypertension ,Rats ,Disease Models, Animal ,embryonic structures ,DNA methylation ,Pulmonary artery ,Cancer research ,business ,Research Article - Abstract
DNA methyltransferase 3B is identified as a protective target against pulmonary vascular remodeling., DNA methylation plays critical roles in vascular pathology of pulmonary hypertension (PH). The underlying mechanism, however, remains undetermined. Here, we demonstrate that global DNA methylation was elevated in the lungs of PH rat models after monocrotaline administration or hypobaric hypoxia exposure. We showed that DNA methyltransferase 3B (DNMT3B) was up-regulated in both PH patients and rodent models. Furthermore, Dnmt3b−/− rats exhibited more severe pulmonary vascular remodeling. Consistently, inhibition of DNMT3B promoted proliferation/migration of pulmonary artery smooth muscle cells (PASMCs) in response to platelet-derived growth factor–BB (PDGF-BB). In contrast, overexpressing DNMT3B in PASMCs attenuated PDGF-BB–induced proliferation/migration and ameliorated hypoxia-mediated PH and right ventricular hypertrophy in mice. We also showed that DNMT3B transcriptionally regulated inflammatory pathways. Our results reveal that DNMT3B is a previously undefined mediator in the pathogenesis of PH, which couples epigenetic regulations with vascular remodeling and represents a therapeutic target to tackle PH.
- Published
- 2020