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Cellular senescence impairs the reversibility of pulmonary arterial hypertension
Open accessAbstract
Pulmonary arterial hypertension (PAH) in congenital cardiac shunts can be reversed by hemodynamic unloading (HU) through shunt closure. However, this reversibility potential is lost beyond a certain point in time. The reason why PAH becomes irreversible is unknown. In this study, we used MCT+shunt-induced PAH in rats to identify a dichotomous reversibility response to HU, similar to the human situation. We compared vascular profiles of reversible and irreversible PAH using RNA sequencing. Cumulatively, we report that loss of reversibility is associated with a switch from a proliferative to a senescent vascular phenotype and confirmed markers of senescence in human PAH-CHD tissue. In vitro, we showed that human pulmonary endothelial cells of patients with PAH are more vulnerable to senescence than controls in response to shear stress and confirmed that the senolytic ABT263 induces apoptosis in senescent, but not in normal, endothelial cells. To support the concept that vascular cell senescence is causal to the irreversible nature of end-stage PAH, we targeted senescence using ABT263 and induced reversal of the hemodynamic and structural changes associated with severe PAH refractory to HU. The factors that drive the transition from a reversible to irreversible pulmonary vascular phenotype could also explain the irreversible nature of other PAH etiologies and provide new leads for pharmacological reversal of end-stage PAH.
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“Van der Feen and colleagues 36 showed that intraperitoneal administration of ABT263 (10 mg/kg daily for 7 days) reversed vascular remodelling and improved pulmonary haemodynamics in the end stage of shuntinduced pulmonary arterial hypertension in a rat model.36”
From The costs and benefits of senotherapeutics for human health (2022) · cites this paper as [36]
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The senescence-associated secretory phenotype: the dark side of tumor suppression
Coppé, J.-P., Desprez, P.-Y., Krtolica, A., & Campisi, J. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-121808-102144 · Cited by 5,206
Cellular senescence in aging and age-related disease: from mechanisms to therapy
Childs, B. G., Durik, M., Baker, D. J., & van Deursen, J. M. (2015) · Nature Medicine · doi:10.1038/nm.4000 · Cited by 2,363
Cellular senescence mediates fibrotic pulmonary disease
Schafer, M. J., White, T. A., Iijima, K., Haak, A. J., Ligresti, G., Atkinson, E. J., Oberg, A. L., Birch, J., Salmonowicz, H., Zhu, Y., et al. (2017) · Nature Communications · doi:10.1038/ncomms14532 · Cited by 1,613
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Mechanisms and functions of cellular senescence
Herranz, N., & Gil, J. (2018) · Journal of Clinical Investigation · doi:10.1172/jci95148 · Cited by 1,232
Matrix metalloproteinases and angiogenesis
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Molecular pathogenesis of pulmonary arterial hypertension
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Self-citationStenmark, K. R., Meyrick, B. O., Galiè, N., Mooi, W. J., & McMurtry, I. F. (2009) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00217.2009 · Cited by 777
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Molecular pathogenesis of pulmonary arterial hypertension
Rabinovitch, M. (2012) · Journal of Clinical Investigation · doi:10.1172/jci60658 · Cited by 672
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Xu, S., Ilyas, I., Little, P. J., Li, H., Kamato, D., Zheng, X., Luo, S., Li, Z., Liu, P., Han, J., et al. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000096 · Cited by 1,205
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Metadata
- Authors
- van der Feen, D. E., Bossers, G. P. L., Hagdorn, Q. A. J., Moonen, J.-R., Kurakula, K., Szulcek, R., Chappell, J., Vallania, F., Donato, M., Kok, K., Kohli, J. S., Petersen, A. H., van Leusden, T., Demaria, M., Goumans, M.-J. T. H., De Boer, R. A., Khatri, P., Rabinovitch, M., Berger, R. M. F., & Bartelds, B.
- Affiliations
- Center for Congenital Heart Diseases, University Medical Center Groningen, 9713 GZ Groningen, Netherlands.
- University Medical Center Groningen (NL)
- Stanford Medicine (US)
- Leiden University Medical Center (NL)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- European Research Institute for the Biology of Ageing, 9700 AD Groningen, Netherlands.
- Department of Experimental Cardiology, University Medical Center Groningen, 9713 GZ Groningen, Netherlands.
- ORCID
- van der Feen, Diederik E.
- Bossers, Guido P. L.
- Hagdorn, Quint A. J.
- Moonen, Jan-Renier
- Kurakula, Kondababu
- Szulcek, Robert
- Chappell, James
- Vallania, Francesco
- Donato, Michele
- Kok, Klaas
- Kohli, Jaskaren S.
- Demaria, Marco
- Goumans, Marie-José T. H.
- De Boer, Rudolf A.
- Khatri, Purvesh
- Rabinovitch, Marlene
- Berger, Rolf M. F.
- Bartelds, Beatrijs
- Venue
- Science Translational Medicine
- Published
- 2020-07-29
- Volume
- 12
- Issue
- 554
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC7891555
- OpenAlex
- W3045698630
- Cited by
- 150
- References
- 51
- Citations by year
- 2026: 22 · 2025: 23 · 2024: 30 · 2023: 22 · 2022: 31 · 2021: 21 · 2020: 1
- FWCI
- 10.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Funders
- Dunlevie Family Fund for Adult Congenital Heart Disease
- Royal Netherlands Academy of Arts and Sciences
- Netherlands Organisation for Health Research and Development
- Dutch Heart Foundation
- Netherlands cardiovascular research initiative (CVON-2012-08)
- Dutch federation of university medical centers
- Integrative omics grant
- NIH NHLI RO
- Sebald Fund
- Ter Meulen Fund
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Genetics (clinical) › Vascular Anomalies and Treatments
- Keywords
- pulmonary arterial hypertension, cellular senescence, congenital heart disease, shunt closure, reversibility, pulmonary endothelial cells, shear stress, senolytic therapy, navitoclax, apoptosis, vascular phenotype
- MeSH terms
- Pulmonary Arterial Hypertension, Animals, Heart Defects, Congenital, Humans, Cellular Senescence, Endothelial Cells, Rats, Familial Primary Pulmonary Hypertension
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