Increased p130 Cas activity induces smooth muscle cell proliferation and migration in idiopathic pulmonary arterial hypertension

Introduction: p130 Cas is a docking protein integrating and regulating extracellular cues and intracellular signaling pathways that controls cell proliferation and motility. Therefore, we hypothesize that p130 Cas contributes to excessive migration and proliferation of PA-SMCs in idiopathic Pulmonary Arterial Hypertension (iPAH). Methods: Protein and phosphorylation levels of p130 Cas were quantified by Western blot in surgically resected lung specimens from iPAH-patients and normal subjects. To assess the functional role of p130 Cas in iPAH and controls, we evaluated migration and proliferation of cultured PA-SMCs with and without p130 Cas inhibition by siRNA. Results: We observed significantly elevated p130 Cas protein expression and activity in iPAH-patients compared to controls. In addition, decreasing p130 Cas signaling by RNA-interference reduced to similar levels both the migration and proliferative potentials of IPAH and control PA-SMCs. The decreased migration and proliferation are respectively mediated by decreased matrix metalloproteinase (MMP)-2 release and by decreased mitogen-activated protein kinase (MAPK) activation. Conclusions: These results demonstrate that p130 Cas protein expression and activity induces PA-SMC proliferation and migration in iPAH, suggesting p130 Cas as an attractive drug target for PAH therapy.