Role of the Fra-2 transcription factor in pulmonary hypertension

Pulmonary hypertension (PH) is a life threatening disease, which is characterized by vasoconstriction of the pulmonary arteries. The increased blood pressure gives rise to remodelling and arterial thickening ultimately leading to right heart failure. Conventional treatment strategies reduce the symptoms of PH, but no causative therapy is available. The pathophysiology of PH remains widely elusive and identifying cellular pathways contributing to the disease would provide new targets for curative therapeutic intervention. We have identified the AP-1 (Activator Protein-1) transcription factor family member Fra-2 as a crucial contributor to the pathogenesis of PH. The over-expression of Fra-2 in mice (Fra-2 TG) leads to vascular remodelling and increased right ventricular systolic pressure, phosphorylation of AKT and enhanced synthesis of collagens. In corroboration of the clinical relevance of this observation, we have determined Fra-2 expression in patient material and Sugen treated rats, a widely accepted animal model of PH. As we confirmed the relevance of our findings in human IPAH disease, the Fra-2 TG constitutes a new model for PH. Here we propose to make use of this novel disease model exploiting the power of mouse genetics for the analysis of the genetic network underlying the pathophysiology of PH. We will investigate the mechanisms by which Fra-2 induces PH by elucidating regulatory mechanisms controlling expression of Fra-2 in PH and analysing Fra-2 target genes, including meprin, for their potential to promote vascular remodelling and inflammatory cell influx. Therefore we will increase the understanding of the pathophysiological mechanisms in PH, which are incompletely understood. This approach might identify novel therapeutic targets for a causative PH treatment, which is an intense medical need.

Role of the Fra-2 transcription factor in pulmonary hypertensionPulmonary hypertension (PH) is a life-threatening disease which is characterized by remodelling and thickening of the pulmonary arteries leading to increased vascular resistance and blood pressure in the lung and ultimately right heart failure. Treatment for patients is only symptomatic, but cannot cure this rare and progressive disease. Moreover, patients with chronic lung diseases, such as lung fibrosis with underlying PH, have worsened prognosis and have no treatment options available. Fra-2 overexpressing mice (Fra-2 TG) are a valuable model to investigate vascular and parenchymal lung involvement in chronic lung diseases. By taking advantage of this model we aimed to delineate how modulation of Fra-2 and its downstream signalling could prevent development of pulmonary hypertension. By using the power of mouse genetics, high-throughput microarray analysis as well as a broad array of cell culture and molecular techniques, we conducted a detailed analysis of the Fra-2 induced pulmonary phenotype with an aim to better understand the underlying pathomechanisms. A detailed profiling of inflammatory mediators in Fra-2 TG mice indicated a type 2-predominant eosinophilic inflammation. Microarray studies supported this finding and further showed upregulation of a wide variety of mucus production and secretion genes and other genes associated with the development of asthma. Indeed, Fra-2 TG mice exhibited an IL-13 dependent asthmatic phenotype with increased airway remodelling, mucus production and airway hyperresponsiveness. Therefore Fra-2 was identified as a novel key molecule not only involved in vascular remodelling but also coordinating multiple aspects of asthma pathogenesis. Furthermore, we found that Fra-2 Tg mice possess increased levels of the pro-inflammatory IL-1 family cytokines in the lung. Inhibiting IL-1 signalling led to worsened lung function with exacerbated inflammation and fibrosis. This worsening was due to a shift towards elevated levels of pro-fibrotic macrophages. Analysis of the Fra-2 effector protease meprin identified its role in the development of PH. Meprin a bound to the cell surface of pulmonary artery endothelial cells where it likely protects from excessive inflammatory cell infiltration. In this project, we identified a novel role of Fra-2 not only in the development of PH, but also in asthma, and delineated key pathways involved in the development of chronic lung diseases. Cumulatively, we have shown the complex role of Fra-2 in coordinating lung homeostasis and that intervening with some of the downstream signalling pathways can have beneficial or detrimental effects. Therefore, this better understanding of the complex biology helps in the development of new potential treatment options in PH and chronic lung diseases in general.