TNF-α Suppresses Prolyl-4-Hydroxylase α1 Expression via the ASK1–JNK–NonO Pathway
Open Access
- 1 August 2007
- journal article
- research article
- Published by Wolters Kluwer Health in Arteriosclerosis, Thrombosis, and Vascular Biology
- Vol. 27 (8), 1760-1767
- https://doi.org/10.1161/atvbaha.107.144881
Abstract
Background— Inflammation is known to contribute to the pathogenesis of vascular diseases in which arterial wall extracellular matrix (ECM) homeostasis is disrupted. Tumor necrosis factor-α (TNF-α), a pivotal cytokine that regulates ECM metabolism by increasing degradation and decreasing production of arterial collagens, is associated with vulnerable plaques and aortic aneurysms. Methods and Results— In the current study, we showed that, when administered in doses of 1 to 100 ng/mL, TNF-α dose-dependently downregulated the expression of prolyl-4-hydroxylase αI [P4Hα(I)]—the rate-limiting subunit for the P4H enzyme essential for procollagen hydroxylation, secretion, and deposition in primary human aortic smooth muscle cells (HASMCs). Using a progressive deletion cloning approach, we characterized the TNF-α–responsive element (TaRE) in the human P4Hα(I) promoter and found that a negative regulatory region at the position of −32 to +18bp is responsible for ≈80% of TNF-α–mediated suppression. Using oligonucleotide-based transcription factor pull-down method in which proteins were resolved in 1-D gel electrophoresis and identified using LC-MS/MS, we identified the NonO protein binds this region. When NonO expression silenced with specific siRNA, we found that 70% of the TNF-α–mediated P4Hα suppression was abolished, which appeared to be mediated by the ASK1-JNK pathway. Conclusions— Our findings define a novel molecular pathway for inflammation associated extracellular matrix dysregulation, which may account for atherosclerotic plaque rupture and aortic aneurysm formation. Further understanding of this pathway may facilitate development of novel therapeutics for vascular diseases.Keywords
This publication has 32 references indexed in Scilit:
- SOCS1 Inhibits Tumor Necrosis Factor-induced Activation of ASK1-JNK Inflammatory Signaling by Mediating ASK1 DegradationJournal of Biological Chemistry, 2006
- The Harms and Benefits of Inflammatory and Immune Responses in Vascular DiseaseStroke, 2006
- Mice With a Deletion in the First Intron of the Col1a1 Gene Develop Age-Dependent Aortic Dissection and RuptureCirculation Research, 2004
- Hydrogen Peroxide Signaling through Tumor Necrosis Factor Receptor 1 Leads to Selective Activation of c-Jun N-terminal KinaseJournal of Biological Chemistry, 2003
- PSF and p54nrb/NonO – multi‐functional nuclear proteinsFEBS Letters, 2002
- Inflammation and AtherosclerosisCirculation, 2002
- Evidence for a role of collagen synthesis in arterial smooth muscle cell migration.JCI Insight, 1998
- Induction of Apoptosis by ASK1, a Mammalian MAPKKK That Activates SAPK/JNK and p38 Signaling PathwaysScience, 1997
- Tumor necrosis factor-alpha and interferon-gamma suppress the activation of human type I collagen gene expression by transforming growth factor-beta 1. Evidence for two distinct mechanisms of inhibition at the transcriptional and posttranscriptional levels.JCI Insight, 1990
- Molecular Biology of Prolyl 4‐HydroxylaseAnnals of the New York Academy of Sciences, 1990