DNA methyltransferase 3B deficiency unveils a new pathological mechanism of pulmonary hypertension.

Abstract

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.

• Authors: Yi Yan, Yang-Yang He, Xin Jiang, Yong Wang, Ji-Wang Chen, Jun-Han Zhao, Jue Ye, Tian-Yu Lian, Xu Zhang, Ru-Jiao Zhang, Dan Lu, Shan-Shan Guo, Xi-Qi Xu, Kai Sun, Su-Qi Li, Lian-Feng Zhang, Xue Zhang, Shu-Yang Zhang, Zhi-Cheng Jing
• Journal: Science advances (Sci Adv) Vol. 6 Issue 50 (12 2020) ISSN: 2375-2548 [Electronic] United States
• PMID: 33298433 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Chemical References

• Becaplermin
• DNA (Cytosine-5-)-Methyltransferases

Topics

• Animals
• Becaplermin (pharmacology)
• Cell Proliferation
• Cells, Cultured
• DNA (Cytosine-5-)-Methyltransferases (genetics)
• Disease Models, Animal
• Humans
• Hypertension, Pulmonary (drug therapy, genetics)
• Hypoxia (genetics)
• Mice
• Rats
• Rats, Sprague-Dawley
• Vascular Remodeling (genetics)
• DNA Methyltransferase 3B