Phosphodiesterase 4D contributes to angiotensin II-induced abdominal aortic aneurysm through smooth muscle cell apoptosis

Gao Ran; Guo Wenjun; Fan Tianfei; Pang Junling; Hou Yangfeng; Feng Xiaohang; Li Bolun; Ge Weipeng; Fan Tianhui; Zhang Tiantian; Lu Jiakai; Jing He; Jin Mu; Yan Chen; Wang Jing

doi:10.1038/s12276-022-00815-y

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자료유형: 학술저널

저자정보: Gao Ran (Peking Union Medical College) Guo Wenjun (Peking Union Medical College) Fan Tianfei (Peking Union Medical College) Pang Junling (Peking Union Medical College) Hou Yangfeng (Peking Union Medical College) Feng Xiaohang (Peking Union Medical College) Li Bolun (Peking Union Medical College) Ge Weipeng (Peking Union Medical College) Fan Tianhui (Peking Union Medical College) Zhang Tiantian (Peking Union Medical College) Lu Jiakai (Capital Medical University) Jing He (Capital Medical University) Jin Mu (Capital Medical University) Yan Chen (University of Rochester) Wang Jing (Peking Union Medical College)

저널정보: 대한생화학·분자생물학회 Experimental and Molecular Medicine Experimental and Molecular Medicine 제54권

발행연도: 2022.8

수록면: 1 - 13 (13page)

DOI: 10.1038/s12276-022-00815-y

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Abdominal aortic aneurysm (AAA) is a permanent expansion of the abdominal aorta that has a high mortality but limited treatment options. Phosphodiesterase (PDE) 4 family members are cAMP-specific hydrolyzing enzymes and have four isoforms (PDE4A-PDE4D). Several pan-PDE4 inhibitors are used clinically. However, the regulation and function of PDE4 in AAA remain largely unknown. Herein, we showed that PDE4D expression is upregulated in human and angiotensin II-induced mouse AAA tissues using RT-PCR, western blotting, and immunohistochemical staining. Furthermore, smooth muscle cell (SMC)-specific Pde4d knockout mice showed significantly reduced vascular destabilization and AAA development in an experimental AAA model. The PDE4 inhibitor rolipram also suppressed vascular pathogenesis and AAA formation in mice. In addition, PDE4D deficiency inhibited caspase 3 cleavage and SMC apoptosis in vivo and in vitro, as shown by bulk RNA-seq, western blotting, flow cytometry and TUNEL staining. Mechanistic studies revealed that PDE4D promotes apoptosis by suppressing the activation of cAMP-activated protein kinase A (PKA) instead of the exchange protein directly activated by cAMP (Epac). Additionally, the phosphorylation of BCL2-antagonist of cell death (Bad) was reversed by PDE4D siRNA in vitro, which indicates that PDE4D regulates SMC apoptosis via the cAMP-PKA-pBad axis. Overall, these findings indicate that PDE4D upregulation in SMCs plays a causative role in AAA development and suggest that pharmacological inhibition of PDE4 may represent a potential therapeutic strategy.

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Gao Ran

소속기관 Peking Union Medical College (PUMC)

주요연구분야 자연과학 > 화학

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Guo Wenjun