Thioredoxin-1 mediates hypoxia-induced pulmonary artery smooth muscle cell proliferation.

Abstract

Pathological pulmonary artery smooth muscle cell (PASMC) proliferation contributes to pulmonary vascular remodeling in pulmonary hypertensive diseases associated with hypoxia. Both the hypoxia-inducible factor (HIF) and phosphatidylinositol 3-kinase (PI3K)/serine/threonine kinase (Akt) pathways have been implicated in hypoxia-induced PASMC proliferation. Thioredoxin-1 (Trx1) is a ubiquitously expressed protein that is involved in redox-dependent signaling via HIF and PI3K-Akt in cancer. The role of Trx1 in PASMC proliferation has not been elucidated. The present studies tested the hypothesis that Trx1 regulates hypoxia-induced PASMC proliferation via HIF and/or PI3K- and Akt-dependent mechanisms. Following exposure to chronic hypoxia, our data indicate that Trx1 activity is increased in adult murine lungs. Furthermore, hypoxia-induced increases in cellular proliferation are correlated with increased Trx1 expression, HIF activation, and Akt activation in cultured human PASMC. Both small-interfering RNA-mediated knockdown and pharmacological Trx1 inhibition attenuated hypoxia-induced PASMC proliferation, HIF activation, and Akt activation. While Trx1 knockdown suppressed hypoxia-induced PI3K-Akt activation in PASMC, PI3K-Akt inhibition prevented hypoxia-induced proliferation but had no effect on hypoxia-induced increases in Trx1 or HIF activation. Thus, our findings indicate that Trx1 contributes to hypoxia-induced PASMC proliferation by modulating HIF activation and subsequent PI3K-Akt activation. These novel data suggest that Trx1 might represent a novel therapeutic target to prevent hypoxic PASMC proliferation.

• Authors: Bernadette Chen, Viktoria E Nelin, Morgan L Locy, Yi Jin, Trent E Tipple
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 305 Issue 5 Pg. L389-95 (Sep 2013) ISSN: 1522-1504 [Electronic] United States
• PMID: 23812635 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Enzyme Inhibitors
• Hypoxia-Inducible Factor 1, alpha Subunit
• Phosphoinositide-3 Kinase Inhibitors
• RNA, Small Interfering
• Thioredoxins
• TXNRD1 protein, human
• Thioredoxin Reductase 1
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Blotting, Western
• Cell Proliferation
• Cells, Cultured
• Enzyme Inhibitors (pharmacology)
• Humans
• Hypoxia (complications, physiopathology)
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Myocytes, Smooth Muscle (metabolism, pathology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Pulmonary Artery (metabolism, pathology)
• RNA, Small Interfering (genetics)
• Signal Transduction
• Thioredoxin Reductase 1 (genetics, metabolism)
• Thioredoxins (antagonists & inhibitors, genetics, metabolism)
• Transcription, Genetic