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PD-1/PD-L1 Provides Protective Role in Hypoxia-Induced Pulmonary Vascular Remodeling.
- Source :
-
Hypertension (Dallas, Tex. : 1979) [Hypertension] 2024 Aug; Vol. 81 (8), pp. 1822-1836. Date of Electronic Publication: 2024 Jun 10. - Publication Year :
- 2024
-
Abstract
- Background: Hypoxia-induced pulmonary hypertension (HPH) is a T helper 17 cell response-driven disease, and PD-1 (programmed cell death 1)/PD-L1 (programmed cell death-ligand 1) inhibitor-associated pulmonary hypertension has been reported recently. This study is designed to explore whether the PD-1/PD-L1 pathway participates in HPH via regulating endothelial dysfunction and T helper 17 cell response.<br />Methods: Lung tissue samples were obtained from eligible patients. Western blotting, immunohistochemistry, and immunofluorescence techniques were used to assess protein expression, while immunoprecipitation was utilized to detect ubiquitination. HPH models were established in C57BL/6 WT (wild-type) and PD-1 <superscript>-/-</superscript> mice, followed by treatment with PD-L1 recombinant protein. Adeno-associated virus vector delivery was used to upregulate PD-L1 in the endothelial cells. Endothelial cell function was assessed through assays for cell angiogenesis and adhesion.<br />Results: Expression of the PD-1/PD-L1 pathway was downregulated in patients with HPH and mouse models, with a notable decrease in PD-L1 expression in endothelial cells compared with the normoxia group. In comparison to WT mice, PD-1 <superscript>-/-</superscript> mice exhibited a more severe HPH phenotype following exposure to hypoxia, However, administration of PD-L1 recombinant protein and overexpression of PD-L1 in lung endothelial cells mitigated HPH. In vitro, blockade of PD-L1 with a neutralizing antibody promoted endothelial cell angiogenesis, adhesion, and pyroptosis. Mechanistically, hypoxia downregulated PD-L1 protein expression through ubiquitination. Additionally, both in vivo and in vitro, PD-L1 inhibited T helper 17 cell response through the PI3K (phosphoinositide 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin) pathway in HPH.<br />Conclusions: PD-1/PD-L1 plays a role in ameliorating HPH development by inhibiting T helper 17 cell response through the PI3K/AKT/mTOR pathway and improving endothelial dysfunction, suggesting a novel therapeutic indication for PD-1/PD-L1-based immunomodulatory therapies in the treatment of HPH.<br />Competing Interests: None.
- Subjects :
- Animals
Mice
Humans
Male
Hypertension, Pulmonary metabolism
Hypertension, Pulmonary etiology
Mice, Inbred C57BL
Disease Models, Animal
Endothelial Cells metabolism
Signal Transduction physiology
Mice, Knockout
Female
Lung metabolism
Lung pathology
B7-H1 Antigen metabolism
B7-H1 Antigen genetics
Programmed Cell Death 1 Receptor metabolism
Programmed Cell Death 1 Receptor genetics
Hypoxia metabolism
Vascular Remodeling physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4563
- Volume :
- 81
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Hypertension (Dallas, Tex. : 1979)
- Publication Type :
- Academic Journal
- Accession number :
- 38853755
- Full Text :
- https://doi.org/10.1161/HYPERTENSIONAHA.123.22393