Signal Transducers and Activators of Transcription-3/Pim1 Axis Plays a Critical Role in the Pathogenesis of Human Pulmonary Arterial Hypertension
- 22 March 2011
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation
- Vol. 123 (11), 1205-1215
- https://doi.org/10.1161/circulationaha.110.963314
Abstract
Background—: Pulmonary artery hypertension (PAH) is a proliferative disorder associated with enhanced pulmonary artery smooth muscle cell proliferation and suppressed apoptosis. The sustainability of this phenotype required the activation of a prosurvival transcription factor like signal transducers and activators of transcription-3 (STAT3) and nuclear factor of activated T cell (NFAT). Because these factors are implicated in several physiological processes, their inhibition in PAH patients could be associated with detrimental effects. Therefore, a better understanding of the mechanism accounting for their expression/activation in PAH pulmonary artery smooth muscle cells is of great therapeutic interest. Methods and Results—: Using multidisciplinary and translational approaches, we demonstrated that STAT3 activation in both human and experimental models of PAH accounts for the expression of both NFATc2 and the oncoprotein kinase Pim1, which trigger NFATc2 activation. Because Pim1 expression correlates with the severity of PAH in humans and is confined to the PAH pulmonary artery smooth muscle cell, Pim1 was identified as an attractive therapeutic target for PAH. Indeed, specific Pim1 inhibition in vitro decreases pulmonary artery smooth muscle cell proliferation and promotes apoptosis, all of which are sustained by NFATc2 inhibition. In vivo, tissue-specific inhibition of Pim1 by nebulized siRNA reverses monocrotaline-induced PAH in rats, whereas Pim1 knockout mice are resistant to PAH development. Conclusion—: We demonstrated for the first time that inhibition of the inappropriate activation of STAT3/Pim1 axis is a novel, specific, and attractive therapeutic strategy to reverse PAH.This publication has 50 references indexed in Scilit:
- Different Effects of Angiotensin II and Angiotensin-(1-7) on Vascular Smooth Muscle Cell Proliferation and MigrationPLOS ONE, 2010
- ENCODE whole-genome data in the UCSC Genome BrowserNucleic Acids Research, 2009
- Evidence of Dysfunction of Endothelial Progenitors in Pulmonary Arterial HypertensionAmerican Journal of Respiratory and Critical Care Medicine, 2009
- Resveratrol Prevents Monocrotaline-Induced Pulmonary Hypertension in RatsHypertension, 2009
- RhoA/Rho-kinase signaling: a therapeutic target in pulmonary hypertensionVascular Health and Risk Management, 2009
- PIM-1–specific mAb suppresses human and mouse tumor growth by decreasing PIM-1 levels, reducing Akt phosphorylation, and activating apoptosisJCI Insight, 2009
- The PIM1 Kinase Is a Critical Component of a Survival Pathway Activated by Docetaxel and Promotes Survival of Docetaxel-treated Prostate Cancer CellsPublished by Elsevier BV ,2008
- Integration of External Signaling Pathways with the Core Transcriptional Network in Embryonic Stem CellsCell, 2008
- The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targetedProceedings of the National Academy of Sciences of the United States of America, 2007
- Up-regulation of a serine–threonine kinase proto-oncogene Pim-1 in oral squamous cell carcinomaInternational Journal of Oral & Maxillofacial Surgery, 2006