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Updated: May 9, 2026
08:02
Isolation of Pulmonary Artery Smooth Muscle Cells from Neonatal Mice
Published on: October 19, 2013
NICD4/USP8-Positive Feedback Loop Contributes to the Development of Hypoxic Pulmonary Hypertension
Mingzhou Guo1,2, Ke Li1,2, Yuchen Huang1,2
1Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (M.G., K.L., Y. Huang, X.W., Y. He, J.Z., X. Liu, X. Li).
Hypertension (Dallas, Tex. : 1979)
|May 8, 2026
Summary
A novel feedback loop involving NICD4 and USP8 drives hypoxic pulmonary hypertension (HPH). Targeting this loop by inhibiting USP8 offers a potential therapeutic strategy for HPH and vascular remodeling.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Cellular Biology
Background:
- Hypoxic pulmonary hypertension (HPH) is a vascular remodeling disease with poor prognosis.
- The NOTCH4 intracellular domain (NICD4) in pulmonary artery smooth muscle cells (PASMCs) is implicated in HPH pathogenesis.
- The precise regulatory mechanisms of NICD4 in HPH remain unclear.
Purpose of the Study:
- To elucidate the regulatory mechanism of NICD4 in HPH.
- To identify proteins interacting with NICD4 in PASMCs.
- To investigate the role of USP8 in HPH development.
Main Methods:
- Coimmunoprecipitation and mass spectrometry to identify NICD4-binding proteins.
- In vivo studies using smooth muscle cell-specific Usp8 knockout mice (Usp8Acta2-/-).
- In vitro studies using cultured PASMCs and pharmacological inhibition of USP8 with DUB-IN-2.
Main Results:
- USP8 was upregulated in HPH patient tissues, HPH models, and hypoxic PASMCs.
- Usp8 deficiency or USP8 inhibition attenuated HPH development.
- USP8 knockdown suppressed hypoxia-induced PASMC proliferation, migration, and apoptosis resistance by modulating the NICD4-MAPK pathway.
- USP8 deubiquitinates NICD4, maintaining its stability and forming a NICD4/USP8 positive feedback loop.
Conclusions:
- A critical NICD4/USP8-positive feedback loop drives HPH pathogenesis.
- Ubiquitination plays a key role in pulmonary vascular remodeling.
- Targeting this feedback loop is a promising therapeutic strategy for HPH.
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