Endothelial phosphodiesterase 4B inactivation ameliorates endothelial-to-mesenchymal transition and pulmonary hypertension

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外文摘要：Pulmonary hypertension(PH)is a fatal disorder characterized by pulmonary vascular remo-deling and obstruction.The phosphodiesterase 4(PDE4)family hydrolyzes cyclic AMP(cAMP)and is comprised of four subtypes(PDE4A-D).Previous studies have shown the beneficial effects of pan-PDE4 inhibitors in rodent PH;however,this class of drugs is associated with side effects owing to the broad inhibition of all four PDE4 isozymes.Here,we demonstrate that PDE4B is the predominant PDE isozyme in lungs and that it was upregulated in rodent and human PH lung tissues.We also confirmed that PDE4B is mainly expressed in the lung endothelial cells(ECs).Evaluation of PH in Pde4b wild type and knockout mice confirmed that Pde4b is important for the vascular remodeling associated with PH.In vivo EC lineage tracing demonstrated that Pde4b induces PH development by driving endothelial-to-mesenchymal transition(EndMT),and mechanistic studies showed that Pde4b regulates EndMT by antagonizing the cAMP-dependent PKA-CREB-BMPRⅡ axis.Finally,treating PH rats with a PDE4B-specific inhibitor validated that PDE4B inhibition has a significant pharmacological effect in the alleviation of PH.Collectively,our findings indicate a critical role for PDE4B in EndMT and PH,prompting further studies of PDE4B-specific inhibitors as a therapeutic strategy for PH.

外文关键词：

Phosphodiesterase 4BPulmonary hypertensionEndothelial-to-mesenchymal transitionProtein kinase ABone morphogenetic protein receptor ⅡSide effectsLineage tracingVascular remodeling

作者：

Yanjiang Xing、Yangfeng Hou、Tianfei Fan、Ran Gao、Xiaohang Feng、Bolun Li、Junling Pang、Wenjun Guo、Ting Shu、Jinqiu Li、Jie Yang、Qilong Mao、Ya Luo、Xianmei Qi、Peiran Yang、Chaoyang Liang、Hongmei Zhao、Wenhui Chen、Jing Wang、Chen Wang

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作者单位：

State Key Laboratory of Respiratory Health and Multimorbidity,Institute of Basic Medical Sciences,Chinese Academy of Medical Sciences,Peking Union Medical College,Beijing 100005,China

Haihe Laboratory of Cell Ecosystem,Chinese Academy of Medical Sciences and Peking Union Medical College,Tianjin 300051,China

Department of Pharmacy,West China Hospital,Sichuan University,Chengdu 610044,China

Department of Lung Transplantation,National Center for Respiratory Medicine,National Clinical Research Center for Respiratory Diseases,China-Japan Friendship Hospital,Institute of Respiratory Medicine,Chinese Academy of Medical Sciences,Beijing 100029,China

The State Key Laboratory of Complex,Severe,and Rare Diseases,Institute of Basic Medical Sciences,Chinese Academy of Medical Sciences,Department of Pathophysiology,Peking Union Medical College,Beijing 100005,China

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基金：

北京市自然科学基金National High Level of Hospital Clinical Research Funding,ChinaNational Key Research and Development Program of ChinaNational Key Research and Development Program of ChinaChinese Academy of Medical Sciences Innovation Fund for Medical Sciences,ChinaChinese Academy of Medical Sciences Innovation Fund for Medical Sciences,ChinaChinese Academy of Medical Sciences Innovation Fund for Medical Sciences,ChinaChinese Academy of Medical Sciences Innovation Fund for Medical Sciences,ChinaHaihe Laboratory of Cell Ecosystem Innovation Fund,China国家自然科学基金

项目编号：

Z2200192022-PUMCH-D-0022019YFA08017032019YFA08018042022-I2M-JB-0072021-I2M-1-0162021-I2M-1-0492021-I2M-1-00522HHXBSS0001082241004

出版年：

2024

DOI：

10.1016/j.apsb.2024.01.012

药学学报(英文版)

CSTPCD

ISSN：

年,卷(期)：2024.14(4)

参考文献量58