Targeting RUNX1 as a novel treatment modality for pulmonary arterial hypertension.
Targeting RUNX1 as a novel treatment modality for pulmonary arterial hypertension.
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靶向RUNX1作为一种治疗肺动脉高压的新方法。
DOI：
10.1093/cvr/cvac001
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发表时间：
2022-12-29
影响因子：
10.8
通讯作者：
中科院分区：
文献类型：
--
作者：
Pulmonary arterial hypertension (PAH) is a fatal disease without a cure. Previously, we found that transcription factor RUNX1-dependent haematopoietic transformation of endothelial progenitor cells may contribute to the pathogenesis of PAH. However, the therapeutic potential of RUNX1 inhibition to reverse established PAH remains unknown. In the current study, we aimed to determine whether RUNX1 inhibition was sufficient to reverse Sugen/hypoxia (SuHx)-induced pulmonary hypertension (PH) in rats. We also aimed to demonstrate possible mechanisms involved. We administered a small molecule specific RUNX1 inhibitor Ro5-3335 before, during, and after the development of SuHx-PH in rats to investigate its therapeutic potential. We quantified lung macrophage recruitment and activation in vivo and in vitro in the presence or absence of the RUNX1 inhibitor. We generated conditional VE-cadherin-CreERT2; ZsGreen mice for labelling adult endothelium and lineage tracing in the SuHx-PH model. We also generated conditional Cdh5-CreERT2; Runx1(flox/flox) mice to delete Runx1 gene in adult endothelium and LysM-Cre; Runx1(flox/flox) mice to delete Runx1 gene in cells of myeloid lineage, and then subjected these mice to SuHx-PH induction. RUNX1 inhibition in vivo effectively prevented the development, blocked the progression, and reversed established SuHx-induced PH in rats. RUNX1 inhibition significantly dampened lung macrophage recruitment and activation. Furthermore, lineage tracing with the inducible VE-cadherin-CreERT2; ZsGreen mice demonstrated that a RUNX1-dependent endothelial to haematopoietic transformation occurred during the development of SuHx-PH. Finally, tissue-specific deletion of Runx1 gene either in adult endothelium or in cells of myeloid lineage prevented the mice from developing SuHx-PH, suggesting that RUNX1 is required for the development of PH. By blocking RUNX1-dependent endothelial to haematopoietic transformation and pulmonary macrophage recruitment and activation, targeting RUNX1 may be as a novel treatment modality for pulmonary arterial hypertension.
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影响因子：
64.8
作者：
Chen, Michael J.;Yokomizo, Tomomasa;Zeigler, Brandon M.;Dzierzak, Elaine;Speck, Nancy A.
通讯作者：
Speck, Nancy A.
DOI：
10.3390/molecules23061479
发表时间：
2018-06-19
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Lambert M;Jambon S;Depauw S;David-Cordonnier MH
通讯作者：
David-Cordonnier MH
影响因子：
16.6
作者：
Gräf S;Haimel M;Bleda M;Hadinnapola C;Southgate L;Li W;Hodgson J;Liu B;Salmon RM;Southwood M;Machado RD;Martin JM;Treacy CM;Yates K;Daugherty LC;Shamardina O;Whitehorn D;Holden S;Aldred M;Bogaard HJ;Church C;Coghlan G;Condliffe R;Corris PA;Danesino C;Eyries M;Gall H;Ghio S;Ghofrani HA;Gibbs JSR;Girerd B;Houweling AC;Howard L;Humbert M;Kiely DG;Kovacs G;MacKenzie Ross RV;Moledina S;Montani D;Newnham M;Olschewski A;Olschewski H;Peacock AJ;Pepke-Zaba J;Prokopenko I;Rhodes CJ;Scelsi L;Seeger W;Soubrier F;Stein DF;Suntharalingam J;Swietlik EM;Toshner MR;van Heel DA;Vonk Noordegraaf A;Waisfisz Q;Wharton J;Wort SJ;Ouwehand WH;Soranzo N;Lawrie A;Upton PD;Wilkins MR;Trembath RC;Morrell NW
通讯作者：
Morrell NW
影响因子：
9.1
作者：
El Chami, Hala;Hassoun, Paul M.
通讯作者：
Hassoun, Paul M.
影响因子：
2.5
作者：
Alva, JA;Zovein, AC;Iruela-Arispe, ML
通讯作者：
Iruela-Arispe, ML