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

• DOI: 10.1016/j.apsb.2024.01.012
• Publication Date: 2024-01-22T16:53:11Z
• Authors: 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
• Keywords: Knockout mouse

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