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Genomic Insights and Novel PAH Therapies

Joe Garcia


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Conference: 2010 International PHA Conference and Scientific Sessions

Release Date: 06.22.2010

Presentation Type: Scientific Sessions

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Pulmonary arterlial hypertension (PAH), a lethal syndrome characterized by ovstruction of small pulmonary arteris, shares many similarities with cancer pathology and signaling pathways which result in endothelial and smooth muscle cell dysfunction and angioproliferative vasculopathy. Although mutations of the bone morphogenetic protein receptor type 2 gene (BMPR2) have been identified in PAH, clearly, other genetic polymorphisms and environmental factors are necessary to initiate the pathological sequence that leads to disease. Therapies for PAH remain limited, however, protein kinase inhibitors which target angiogenic growth factors as well as key signaling intermediates involved in mediating MAP kinase pathway activation such as Raf-1-kinase have been proposed as potentially novel therapies. We recently conducted pre-clinical studies with the protein kinase inhibitor, sorafenib, as a potentially novel treatment for sever pulmonary hypertension with the MAPK cascade a potential canonical target profoundly effective vascular cytoskeletal rearrangements and remodeling. We additionally employed high throughput technologies to analyze gene expression profiles of lung tissue obtained from PAH patients and rodent models of PAH. The vascular endothelial groth factor (VEGF) receptor tyrosine kinase inhibitor, sorafenib, an oral multi-kinase inhibitor of the protein kinases PKC/Ras, Raf, MEK-1,2, ERK-1,2 and Elk-1 signaling pathway and an FDA-approved cancer therapy, was shown to alter PAH pathobiology in two pre-clincal PAH rodent models attenuated PA remodeling and RV hemodynamics with remarkable reductions in medical wall thickening luminal obliteration and plexiform lesion formation in rat lungs. Bioinformatic analyses of expression profiles revealed differentially-regulated transcript sets likely involved in the development of the severe PAH phenotype as well as significantly overrepresented biological processes. Sorafenib regulated the majority of biological processes implicated in both models of PAH with several genes identified which were previously reported to be involved in PAH biological pathways. These studies revealed biochemical and genomic evidence supporting the potential involvement of the MAPK cascade system, TGF 3 and cytoskeletal proteins such as caldesmon and MLCK as key participants in the cytoskeletal rearrangement present during pulmonary hypertension-induced remodeling and proliferation in endothelium. these represent potentially novel molecular targets for altering the devastating clinical course of patients with PH.