期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 12, 期 554, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aaw4974
关键词
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资金
- Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation
- Dutch Federation of University Medical Centres
- Netherlands Organization for Health Research and Development
- Royal Netherlands Academy of Sciences [CVON-Phaedra 2012-08]
- Sebald Fund
- Ter Meulen Fund (Royal Netherlands Academy of Sciences)
- Dutch Heart Foundation [NHS2013-T091]
- Integrative Omics grant
- NIH NHLBI RO
- Dunlevie Professorship
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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