Loss of cAbl Tyrosine Kinase in Pulmonary Arterial Hypertension Causes Dysfunction of Vascular Endothelial Cells.

Abstract

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 Sugen + hypoxia 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.

• Authors: Benjamin Le Vely, Carole Phan, Nihel Berrebeh, Raphaël Thuillet, Mina Ottaviani, Mustapha Kamel Chelgham, Marie-Camille Chaumais, Larbi Amazit, Marc Humbert, Alice Huertas, Christophe Guignabert, Ly Tu
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 67 Issue 2 Pg. 215-226 (08 2022) ISSN: 1535-4989 [Electronic] United States
• PMID: 35550008 (Publication Type: Journal Article)

Chemical References

• Monocrotaline
• Protein-Tyrosine Kinases

Topics

• Animals
• Disease Models, Animal
• Endothelial Cells (metabolism)
• Familial Primary Pulmonary Hypertension (metabolism)
• Humans
• Monocrotaline
• Protein-Tyrosine Kinases (metabolism)
• Pulmonary Arterial Hypertension
• Pulmonary Artery (metabolism)
• Rats