Eliminating Senescent Cells Can Promote Pulmonary Hypertension Development and Progression
Abstract
Background: Senescent cells (SCs) are involved in proliferative disorders, but their role in pulmonary hypertension remains undefined. We investigated SCs in patients with pulmonary arterial hypertension and the role of SCs in animal pulmonary hypertension models. Methods: We investigated senescence (p16, p21) and DNA damage (γ-H2AX, 53BP1) markers in patients with pulmonary arterial hypertension and murine models. We monitored p16 activation by luminescence imaging in p16-luciferase (p16 LUC/+ ) knock-in mice. SC clearance was obtained by a suicide gene (p16 promoter–driven killer gene construct in p16-ATTAC mice), senolytic drugs (ABT263 and cell-permeable FOXO4-p53 interfering peptide [FOXO4-DRI]), and p16 inactivation in p16 LUC/LUC mice. We investigated pulmonary hypertension in mice exposed to normoxia, chronic hypoxia, or hypoxia+Sugen, mice overexpressing the serotonin transporter (SM22-5-HTT + ), and rats given monocrotaline. Results: Patients with pulmonary arterial hypertension compared with controls exhibited high lung p16, p21, and γ-H2AX protein levels, with abundant vascular cells costained for p16, γ-H2AX, and 53BP1. Hypoxia increased thoracic bioluminescence in p16 LUC/+ mice. In wild-type mice, hypoxia increased lung levels of senescence and DNA-damage markers, senescence-associated secretory phenotype components, and p16 staining of pulmonary endothelial cells (P-ECs, 30% of lung SCs in normoxia), and pulmonary artery smooth muscle cells. SC elimination by suicide gene or ABT263 increased the right ventricular systolic pressure and hypertrophy index, increased vessel remodeling (higher dividing proliferating cell nuclear antigen–stained vascular cell counts during both normoxia and hypoxia), and markedly decreased lung P-ECs. Pulmonary hemodynamic alterations and lung P-EC loss occurred in older p16 LUC/LUC mice, wild-type mice exposed to Sugen or hypoxia+Sugen, and SM22-5-HTT + mice given either ABT263 or FOXO4-DRI, compared with relevant controls. The severity of monocrotaline-induced pulmonary hypertension in rats was decreased slightly by ABT263 for 1 week but was aggravated at 3 weeks, with loss of P-ECs. Conclusions: Elimination of senescent P-ECs by senolytic interventions may worsen pulmonary hemodynamics. These results invite consideration of the potential impact on pulmonary vessels of strategies aimed at controlling cell senescence in various contexts.
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Senescent cells have important physiological roles and their clearance may be detrimental in certain conditions.
“It should be noted, however, that senescent cells also have important physiological roles and that their clearance may be detrimental in certain conditions3–5.”
From Spatial mapping of cellular senescence: emerging challenges and opportunities (2023) · cites this paper as [4]
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Spatial mapping of cellular senescence: emerging challenges and opportunities
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“The advantages of FISH-based methodologies are (1) high-plex number above hundreds, (2) high detection efficiency and high number of transcripts per cell in comparison with sequencing-based technologies, (3) single-cellular to subcellular resolution owing to advancement in machine learning-based segmentation algorithm…”
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“Targeted clearance of senescent cells with senolytics can mitigate disease severity and increase healthspan 7 – 10 , but their elimination may exacerbate disease in some contexts 11 .”
- Authors
- Born, E., Lipskaia, L., Breau, M., Houssaini, A., Beaulieu, D., Marcos, E., Pierre, R., Do Cruzeiro, M., Lefevre, M., Derumeaux, G., Bulavin, D. V., Delcroix, M., Quarck, R., Reen, V., Gil, J., Bernard, D., Flaman, J.-M., Adnot, S., & Abid, S.
- Affiliations
- Inserm (FR)
- Centre National de la Recherche Scientifique (FR)
- INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, FHU SENEC, AP-HP, Créteil, France; Université Paris-Est Créteil (UPEC), France (E.B., L.L., M.B., A.H., D.P.B., E.M., G.D., S. Adnot, S. Abid).
- Plate-forme de Recombinaison Homologue, Institut Cochin, INSERM, Paris, France (R.P., M.D.-C.).
- Institut Mutualiste Montsouris, Département anatomopathologie, Paris, France (M.L.).
- Institut de Recherche sur le Cancer et le Vieillissement de Nice (FR)
- KU Leuven (BE)
- MRC London Institute of Medical Sciences (GB)
- MRC London Institute of Medical Sciences (LMS), United Kingdom (V.R., J.G.).
- Liaquat University of Medical & Health Sciences (PK)
- Corresponding author
- Born, Emmanuelle
- Lipskaia, Larissa
- Breau, Marielle
- ORCID
- Venue
- Circulation
- Published
- 2023-02-21
- Volume
- 147
- Issue
- 8
- Pages
- 650-666
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W4311392380
- Cited by
- 148
- References
- 45
- Citations by year
- 2026: 38 · 2025: 48 · 2024: 42 · 2023: 20
- FWCI
- 17.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Lirias (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-20-CE14-0023, ANR-18-CE14-0031)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Pathology and Forensic Medicine › Systemic Sclerosis and Related Diseases
- Keywords
- senescent cells, pulmonary arterial hypertension, senolytics, navitoclax, senescence-associated secretory phenotype, p16, p21, DNA damage, hypoxia, senolytic therapy, vascular endothelial cells, pulmonary artery smooth muscle cells, monocrotaline, serotonin transporter, right ventricular systolic pressure, vascular remodeling
- MeSH terms
- Pulmonary Arterial Hypertension, Senotherapeutics, Aniline Compounds, Animals, Hypoxia, Hypertension, Pulmonary, Pulmonary Artery, Sulfonamides, Monocrotaline, Cellular Senescence, Endothelial Cells, Mice, Rats, Forkhead Transcription Factors, Familial Primary Pulmonary Hypertension
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