FLI1 in Pulmonary Arterial Hypertension

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Pulmonary arterial hypertension (PAH) is a rare and devastating disease resulting in pulmonary arterial remodeling, right heart failure and death. While there are FDA-approved therapies, none is curative. It has been recognized for years that growth factors, such as platelet-derived growth factor and fibroblast growth factor, act through tyrosine kinase receptors to promote pulmonary vascular remodeling in PAH. Imatinib, a non-specific tyrosine kinase inhibitor showed promise in animal models of PAH and several case reports demonstrated cures of PAH with imatinib. A Phase III clinical trial of imatinib in PAH showed marked improvement in exercise capacity in some patients but did not receive FDA approval because the drug was not well tolerated. We sought to understand novel mechanisms of imatinib effect in PAH. In preliminary data, we administered imatinib to mice that express a human mutation that is known to cause heritable forms of PAH (bone morphogenetic receptor type 2, BMPR2) and tested changes in plasma proteomics as a novel way of detecting key drug effects in a manner that could be translated to humans and may lend mechanistic insight. imatinib altered several proteins in the plasma with Friend leukemia virus integration 1 (Fli1) being the most significantly changed protein. Fli1 is a transcription factor whose function is increased after c-Abl engagement by imatinib. Interestingly, Fli1 deficiency is well described to play a role in the vasculopathy of the skin of patients with scleroderma, a condition closely associated with PAH. it is unknown if Fli1 deficiency plays a role in PAH however. We have used imatinib as a tool to understand mechanisms of pulmonary vascular dysfunction in PAH and uncovered that Fli1 may play a key role. Our overarching hypothesis is that Fli1 deficiency contributes to PAH development through disruption of endothelial barrier function and that restoration of Fli1 will restore endothelial function and improve PAH. We propose the following aims to test this hypothesis: Aim 1. Test the hypothesis endothelial barrier function is impaired in PAH and that increased Fli1 expression through imatinib exposure restores endothelial function in PAH. We will use cultured BMPR2 or control endothelial cells with and without imatinib and/or Fli1 siRNA to test barrier function and the role of Fli1 in regulating endothelial barrier function. Aim 2. Test the hypothesis that Fli1 deficiency is a rodent model of PAH, enhances pulmonary vascular disease in a rodent model of PAH and that Fli1 overexpression prevents rodent PAH. This aim will generate two mouse models: inducible global Fli1 knockout and inducible global overexpression of Fli1. We will determine these models exacerbate or improve an accepted rodent PAH model, Sugen+Hypoxia, and test for pulmonary vascular leak in these models. This proposal will generate necessary tools to study the role of FLI1 in PAH. In the long term, this work will develop novel, well-tolerated disease modifying therapies for this rare and highly morbid disease.