DNA methyltransferase 3B deficiency unveils a new pathological mechanism of pulmonary hypertension.
DNA methyltransferase 3B deficiency unveils a new pathological mechanism of pulmonary hypertension.
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DNA甲基转移酶3B缺陷揭示了肺动脉高压的新病理机制
DOI：
10.1126/sciadv.aba2470
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发表时间：
2020-12
期刊：
影响因子：
13.6
通讯作者：
Jing ZC
中科院分区：
文献类型：
--
作者：
Yan Y;He YY;Jiang X;Wang Y;Chen JW;Zhao JH;Ye J;Lian TY;Zhang X;Zhang RJ;Lu D;Guo SS;Xu XQ;Sun K;Li SQ;Zhang LF;Zhang X;Zhang SY;Jing ZC
DNA甲基转移酶3B被确定为肺血管重塑的保护性靶点。DNA甲基化在肺动脉高压的血管病理中起着重要作用。然而，其内在机制仍不确定。在这里，我们表明，全球DNA甲基化升高肺PH大鼠模型后，野百合碱管理或低压缺氧暴露。我们发现DNA甲基转移酶3B（DNMT 3B）在PH患者和啮齿动物模型中均上调。此外，Dnmt 3b −/−大鼠表现出更严重的肺血管重构。一致地，抑制DNMT 3B促进肺动脉平滑肌细胞（PASMC）响应于血小板衍生生长因子-BB（PDGF-BB）的增殖/迁移。相反，在PASMCs中过表达DNMT 3B减弱了PDGF-BB诱导的增殖/迁移，并改善了小鼠缺氧介导的PH和右心室肥大。我们还发现，DNMT 3B转录调节炎症通路。我们的研究结果表明，DNMT 3B是PH发病机制中以前未定义的介质，其将表观遗传调节与血管重塑偶联，并代表了治疗PH的治疗靶点。
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.
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影响因子：
2.1
作者：
Koskenvuo, Juha W.;Mirsky, Rachel;Zhang, Yan;Angeli, Franca S.;Jahn, Sarah;Alastalo, Tero-Pekka;Schiller, Nelson B.;Boyle, Andrew J.;Chatterjee, Kanu;De Marco, Teresa;Yeghiazarians, Yerem
通讯作者：
Yeghiazarians, Yerem
影响因子：
37.8
作者：
Hopper RK;Moonen JR;Diebold I;Cao A;Rhodes CJ;Tojais NF;Hennigs JK;Gu M;Wang L;Rabinovitch M
通讯作者：
Rabinovitch M
DOI：
10.1096/fj.201500088r
发表时间：
2016-05
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
--
作者：
Mikolajczyk TP;Nosalski R;Szczepaniak P;Budzyn K;Osmenda G;Skiba D;Sagan A;Wu J;Vinh A;Marvar PJ;Guzik B;Podolec J;Drummond G;Lob HE;Harrison DG;Guzik TJ
通讯作者：
Guzik TJ
影响因子：
16.6
作者：
Dai J;Zhou Q;Chen J;Rexius-Hall ML;Rehman J;Zhou G
通讯作者：
Zhou G
DOI：
10.1164/rccm.2012112
发表时间：
2002-02-15
影响因子：
24.7
作者：
Dorfmüller, P;Zarka, V;Humbert, M
通讯作者：
Humbert, M