Targeting cell motility in pulmonary arterial hypertension.

Abstract

Pulmonary artery smooth muscle cells (PASMC), in pulmonary arterial hypertension (PAH), contribute to obliterative vascular remodelling and are characterised by enhanced proliferation, suppressed apoptosis and, a much less studied, increased migration potential. One of the major proteins that regulate cell migration is focal adhesion kinase (FAK), but its role in PAH is not fully understood. We hypothesised that targeting cell migration by FAK inhibition may be a new therapeutic strategy in PAH. In vivo, inhalation of FAK-siRNA (n=5) or oral delivery of PF-228 (FAK inhibitor PF-573 228; n=5) inhibited rat monocrotaline induced PAH, improving the haemodynamics, vascular remodelling (media thickness), and right ventricular hypertrophy. In vitro, FAK was activated in PAH human lungs (n=8) or PASMC when compared to those form healthy subjects (Western blot, n=5), in a Src-dependent manner, as it was reversed by the specific Src inhibitor PP2. The degree of FAK phosphorylation at Y576 correlated positively with pulmonary vascular resistance in PAH patients. FAK inhibition (siRNA, PF-228 and PP2) in PAH-PASMCs induced a fivefold increase in apoptosis (percentage of terminal deoxynucleotidyl transferase dUTP nick end labelling), a 2.5-fold decrease in proliferation (%Ki67), an 18% decrease in cell migration (colorimetric assay) and a 50% decrease in cell invasion (wound healing). Suppressing PASMC migration by FAK inhibition inhibits PAH progression and may open a new therapeutic window in PAH.

• Authors: Roxane Paulin, Jolyane Meloche, Audrey Courboulin, Caroline Lambert, Alois Haromy, Antony Courchesne, Pierre Bonnet, Steeve Provencher, Evangelos D Michelakis, Sébastien Bonnet
• Journal: The European respiratory journal (Eur Respir J) Vol. 43 Issue 2 Pg. 531-44 (Feb 2014) ISSN: 1399-3003 [Electronic] England
• PMID: 23845719 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Small Interfering
• Focal Adhesion Protein-Tyrosine Kinases

Topics

• Adolescent
• Adult
• Animals
• Apoptosis
• Cell Movement
• Familial Primary Pulmonary Hypertension
• Female
• Focal Adhesion Protein-Tyrosine Kinases (metabolism)
• Gene Expression Regulation
• Humans
• Hypertension, Pulmonary (physiopathology)
• Lung (pathology)
• Male
• Middle Aged
• Phosphorylation
• RNA, Small Interfering (metabolism)
• Rats
• Rats, Sprague-Dawley
• Young Adult