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

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 

作者机构：State Key Laboratory of Respiratory Health and MultimorbidityInstitute of Basic Medical SciencesChinese Academy of Medical SciencesPeking Union Medical CollegeBeijing 100005China Department of Lung TransplantationNational Center for Respiratory MedicineNational Clinical Research Center for Respiratory DiseasesChina–Japan Friendship HospitalInstitute of Respiratory MedicineChinese Academy of Medical SciencesBeijing 100029China Haihe Laboratory of Cell EcosystemChinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin 300051China The State Key Laboratory of ComplexSevereand Rare DiseasesInstitute of Basic Medical SciencesChinese Academy of Medical SciencesDepartment of PathophysiologyPeking Union Medical CollegeBeijing 100005China Department of PharmacyWest China HospitalSichuan UniversityChengdu 610044China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2024年第14卷第4期

页      面：1726-1741页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学] 

基　　金：This work was supported by Beijing Natural Science Foundation[Z220019 to Jing Wang,China] National High Level of Hospital Clinical Research Funding[2022-PUMCH-D-002 to Jing Wang,China] National Key Research and Development Program of China Grants[2019YFA0801703 and 2019YFA0801804 to Jing Wang] Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences[2022-I2M-JB-007 to Chen Wang,2021-I2M-1-016 to Hongmei Zhao,2021-I2M-1-049 to Jing Wang,2021-I2M-1-005 to Yanjiang Xing,China] Haihe Laboratory of Cell Ecosystem Innovation Fund[22HHXBSS00010 to Jing Wang,China] National Natural Science Foundation of China[82241004 to Jing Wang] 

主　　题：Phosphodiesterase 4B Pulmonary hypertension Endothelial-to-mesenchymal transition 

摘      要：Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling 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.