Abstract 16712: Focal Adhesion Kinase: A Putative Therapeutic Target for the Treatment of Pulmonary Arterial Hypertension
Background: Pulmonary arterial hypertension (PAH) is characterized by enhanced pulmonary artery smooth muscle cells (PASMC) proliferation, migration and suppressed apoptosis. This phenotype is attributed in part to the sustained activation of the neoplasic axis c-Src/STAT3. In cancer, c-Src enhances focal adhesion kinase activation (FAK), a signaling hub implicated in the sustainability of cell proliferation, survival and motility, in part by potently inducing STAT family of proteins activation. Recently FAK inhibition has been proposed as a new therapeutic intervention in cancer. We hypothesized that FAK inhibition in PAH will decrease the activation of STAT3 axis decreasing PASMC proliferation, migration and resistance to apoptosis.
Methods/Results: Using immunoblots (n=3 p<0.05) we showed activation of both c-Src and FAK (phosphorylation on Y416 and Y397 respectively) in human PAH-PASMCs resulting in cSrc/FAK complex formation (FAK phosphorylation on Y576) promoting STAT3 activation (phosphorylation on Y705). All these results were inhibited by 1) Src inhibitor PP2, 2) FAK siRNA. The Src/FAK-dependent activation of STAT3 accounts for 1) PAH-PASMCs mitochondrial hyperpolarization (TMRM n=150 p<0.05), increasing resistance to apoptosis (n=150 p<0.05 TUNEL) 2) increases proliferation by 30% (PCNA & Ki67) 3) increases cell migration (transwell assay, n=3 p<0.05) and invasion (Scratch test n=5 p<0.05) by 25% compared to controls. All these findings were similarly reversed by either Src, FAK and STAT3 inhibitors. Finally, in vivo FAK-siRNA nebulization improves monocrotaline-PAH (n=10 in each group p<0.05) measured by PA pressure, PA wall thickness, right ventricular hypertrophy (Echo & catheterization).
Conclusion: FAK inhibition represents a new therapeutic target for PAH. Currently new FAK inhibitors have been moved to clinic trials to treat cancer. Our findings suggest that these compounds could be useful for the treatment of PAH as well.
- © 2011 by American Heart Association, Inc.