DNA-PKcs participated in hypoxic pulmonary hypertension

Area of Science:

• Cardiovascular Research
• Molecular Biology
• Pulmonary Medicine

Background:

• Hypoxic pulmonary hypertension (HPH) is a severe complication of chronic lung disease.
• DNA damage and repair pathways are implicated in pulmonary arterial hypertension pathogenesis.
• DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a key sensor for DNA damage and repair.

Purpose of the Study:

• To investigate the expression and mechanism of DNA-PKcs in the pathogenesis of HPH.
• To determine the role of DNA-PKcs in pulmonary vascular remodeling under hypoxic conditions.

Main Methods:

• Quantified DNA-PKcs and NOR1 expression in human and rat pulmonary artery tissues and cells using immunohistochemistry, Western blot, and qRT-PCR.
• Assessed protein interactions via Co-immunoprecipitation (Co-IP).
• Evaluated cell proliferation, cell cycle, and apoptosis using CCK-8, EdU, and flow cytometry in vitro, and induced HPH in rat models in vivo.

Main Results:

• DNA-PKcs protein levels were significantly elevated in pulmonary arteries from HPH models and hypoxemic patients.
• Hypoxia upregulated DNA-PKcs in human pulmonary artery smooth muscle cells (PASMCs) in a time-dependent manner.
• Downregulation of DNA-PKcs inhibited PASMC proliferation, induced cell cycle arrest, and reversed hypoxic pulmonary vascular remodeling in vivo by regulating NOR1 and cyclin D1.

Conclusions:

• DNA-PKcs plays a critical role in the development of HPH.
• Targeting DNA-PKcs offers a potential therapeutic strategy for pulmonary vascular remodeling and HPH.