04 February 2019 by Swati Dabral

RASSF1A regulates HIF-1α, triggering a feed forward loop in hypoxia driven Pulmonary Hypertension

Objective:

Hypoxia is an important environmental pressure playing fundamental role in lung pathology. Pulmonary circulation responds uniquely to hypoxia with proliferation of vascular cells and pulmonary hypertension (PH). The mechanisms underlying the vascular responses and regulation of hypoxia-inducible factor 1α (HIF-1α) remain to be elucidated.

Results:

We report that Ras association domain family 1A (RASSF1A), functions as a stabilizing factor for HIF-1α by inhibiting its hydroxylation, leading to increased HIF-1α mediated transactivation of target genes (PDK1, LDHA, HK2), and promoting proliferation and glycolytic shift in hypoxia-exposed pulmonary vascular cells. Hypoxia initially induces reactive oxygen species (ROS) and stabilizes RASSF1A by protein kinase C (PKC)-mediated phosphorylation. RASSF1A transcription is later upregulated by HIF-1α, participating in a positive feedback loop. Consistently, RASSF1A knockout mice do not develop PH in response to hypoxia. Notably, we observed high expression levels of RASSF1A; HIF-1α and HIF-1 target genes in the pulmonary vasculature of patients with PH (IPAH or PH associated with COPD) and in rodent models of PH (hypoxia and hypoxia+SU5416). In addition, we observed that siRNA mediated inhibition of RASSF1A expression reverts the hyperproliferative and glycolytic phenotype of ex-vivo cultured human PH-PASMCs.

Conclusion and Future Outlook:

We propose that a novel feed-forward regulatory interaction of RASSF1A and HIF-1 drive hypoxia-induced PH via regulation of hypoxia induced proliferation and metabolic shift. Taking a step forward, high throughput metabolic profiling of hypoxia exposed pulmonary artery smooth muscle cells in presence of RASSF1A knockdown displayed significant changes in various metabolites from citric acid cycle and glutamine metabolism. In line, mass spectrometry further revealed prolyl hydroxylase 2 (PHD2), Iso-citrate dehydrogenase (IDH) among others as RASSF1A interacting partners. In depth analysis in this direction, will help to reveal the complete picture of hypoxia driven metabolic changes regulated by RASSF1A.

About the author


profile picture of Swati Dabral

Swati Dabral

Postdoctoral fellow

Max-Planck Institute for heart and lung research

Germany

Key Contributors

Swati Dabral 1, Christian Muecke 1, Chanil Valasarajan 1, Mario Schmoranzer 1, Astrid Wietelmann 1, Sven Zukunft 4, Gregg L. Semenza 2, Norbert Weissmann 3 , Ingrid Flemming 4, Friedrich Grimminger 3, Werner Seeger 1,3, Rajkumar Savai 1,3, Soni S. Pullamsetti 1,3 : 1.Max-Planck-Institute for Heart and Lung Research, Department of Lung Development and Remodeling, member of the German Center for Lung Research (DZL), Bad Nauheim, Germany 2.Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, Biological Chemistry, and Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA 3.Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), ECCPS, member of the DZL, Justus-Liebig University, Giessen, Germany 4.Institute for Vascular Signaling, Centre for Molecular Medicine, Goethe University, Frankfurt, Germany


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