@article {DabralOA3008, author = {Swati Dabral and Christian Muecke and Chanil Valsarajan and Mario Schmoranzer and Astrid Wietelmann and Norbert Weissmann and Rajkumar Savai and Werner Seeger and Reinhard Dammann and Soni Savai Pullamsetti}, title = {RASSF1A regulates ROS-HIF axis in hypoxia driven pulmonary hypertension}, volume = {48}, number = {suppl 60}, elocation-id = {OA3008}, year = {2016}, doi = {10.1183/13993003.congress-2016.OA3008}, publisher = {European Respiratory Society}, abstract = {Chronic exposure to alveolar hypoxia results in sustained pulmonary vasoconstriction and pulmonary vascular remodeling leading to development and progression of hypoxia-induced pulmonary hypertension (HPH). Patients with a variety of chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), as well as high altitude residents experience alveolar hypoxia, leading to HPH. We explored the concept whether Ras association domain family protein 1A (RASSF1A), a scaffold protein, can accommodate proteins such as HIF and regulate HIF activity in response to hypoxia and ROS, contributing to pulmonary vascular remodeling.Expression of RASSF1A was analyzed in human PASMCs exposed to different time points of hypoxia, demonstrating a biphasic upregulation of RASSF1A. Under acute hypoxic exposure, RASSF1A was stabilized by NAD(P)H oxidase dependent ROS while under longer hypoxia exposure, RASSF1A expression was regulated by HIF1α. Interestingly, knock down of RASSF1A using si-RASSF1A led to a decreased expression and activity of HIF1α and its downstream target genes (LDHA, PDK1, HK2). Co-immunoprecipitation studies demonstrated RASSF1A interaction with HIF1α under hypoxia. Additional immunoprecipitation studies showed decrease in prolyl hydroxylation and ubiquitination of HIF1α with RASSF1A overexpression. si-RASSF1A decreased hypoxia-induced proliferation of PASMCs and knockout mice of RASSF1A showed attenuated hypoxia-induced PH. Importantly, in pulmonary arteries from IPAH and COPD-PH patients, an increased expression of RASSF1A was observed compared to Donors.We conclude that increased RASSF1A is a critical event in mediating ROS-HIF axis and subsequent metabolic reprograming to aerobic glycolysis.}, issn = {0903-1936}, URL = {https://erj.ersjournals.com/content/48/suppl_60/OA3008}, eprint = {https://erj.ersjournals.com/content}, journal = {European Respiratory Journal} }