期刊
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
卷 67, 期 2, 页码 215-226出版社
AMER THORACIC SOC
DOI: 10.1165/rcmb.2021-0332OC
关键词
pulmonary hypertension; endothelial dysfunction; dasatinib-induced pulmonary hypertension; DNA damage; c-Abelson
资金
- French National Institute for Health and Medical Research (INSERM)
- Universite Paris-Saclay
- Marie Lannelongue Hospital
- Agence Nationale de la Recherche [ANR-16-CE17-0014]
- Fondation Medicale de la Recherche (FRM)
- Departement Hospitalo-Universitaire Thorax Innovation
- Assistance Publique -Hopitaux de Paris, Service de Pneumologie
- Fonds de Recherche en Sant e Respiratoire -Fondation du Souffle
- French PAH patient association (HTAP France)
- Ile-de-France region (ARDoc Health)
- Agence Nationale de la Recherche (ANR) [ANR-16-CE17-0014] Funding Source: Agence Nationale de la Recherche (ANR)
This study found that cAbl concentrations were lower in the endothelium of remodeled pulmonary vessels in patients with PAH. In vitro and in vivo experiments showed that PAH-ECs had lower cAbl expression and activity, as well as altered DNA damage response and capacity of tube formation. Downregulation of cAbl resulted in genomic instability and the failure to form tubes, while upregulation of cAbl reduced DNA damage and apoptosis in PAH-ECs.
Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by the dysfunction of pulmonary endothelial cells (ECs) and obstructive vascular remodeling. cAbl (non-receptor tyrosine kinase c-Abelson) plays central roles in regulating cell-cycle arrest, apoptosis, and senescence after cellular stress. We hypothesized that cAbl is downactivated in experimental and human PAH, thus leading to reduced DNA integrity and angiogenic capacity of pulmonary ECs from patients with PAH (PAH-ECs). We found cAbl and phosphorylated cAbl concentrations to be lower in the endothelium of remodeled pulmonary vessels in the lungs of patients with PAH than in control subjects. Similar observations were obtained for the lungs of Sugen1hypoxia and monocrotaline rats with established pulmonary hypertension. These in situ abnormalities were also replicated in vitro, with cultured PAH-ECs displaying lower cAbl expression and activity and an altered DNA damage response and capacity of tube formation. Downregulation of cAbl by RNA interference in control ECs or its inhibition with dasatinib resulted in genomic instability and the failure to form tubes, whereas upregulation of cAbl with 5-(1,3-diaryl-1H-pyrazol-4-yl) hydantoin reduced DNA damage and apoptosis in PAH-ECs. Finally, we establish the existence of cross-talk between cAbl and bone morphogenetic protein receptor type II. This work identifies the loss of cAbl signaling as a novel contributor to pulmonary EC dysfunction associated with PAH.
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