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CTGF regulated by ATF6 inhibits vascular endothelial inflammation and reduces hepatic ischemia-reperfusion injury.
- Source :
-
Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2024 Dec; Vol. 1870 (8), pp. 167490. Date of Electronic Publication: 2024 Sep 04. - Publication Year :
- 2024
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Abstract
- Vascular endothelial inflammation is crucial in hepatic ischemia-reperfusion injury (IRI). Our previous research has shown that connective tissue growth factor (CTGF), secreted by endothelial cells, protects against acute liver injury, but its upstream mechanism is unclear. We aimed to clarify the protective role of CTGF in endothelial cell inflammation during IRI and reveal the regulation between endoplasmic reticulum stress-induced activating transcription factor 6 (ATF6) and CTGF. Hypoxia/reoxygenation in endothelial cells, hepatic IRI in mice and clinical specimens were used to examine the relationships between CTGF and inflammatory factors and determine how ATF6 regulates CTGF and reduces damage. We found that activating ATF6 promoted CTGF expression and reduced liver damage in hepatic IRI. In vitro, activated ATF6 upregulated CTGF and downregulated inflammation, while ATF6 inhibition had the opposite effect. Dual-luciferase assays and chromatin immunoprecipitation confirmed that activated ATF6 binds to the CTGF promoter, enhancing its expression. Activated ATF6 increases CTGF and reduces extracellular regulated protein kinase 1/2 (ERK1/2) phosphorylation, decreasing inflammatory factors. Conversely, inhibiting ATF6 decreases CTGF and increases the phosphorylation of ERK1/2, increasing inflammatory factor levels. ERK1/2 inhibition reverses this effect. Clinical samples have shown that CTGF increases after IRI, inversely correlating with inflammatory cytokines. Therefore, ATF6 activation during liver IRI enhances CTGF expression and reduces endothelial inflammation via ERK1/2 inhibition, providing a novel target for diagnosing and treating liver IRI.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Humans
Mice
Male
Inflammation metabolism
Inflammation pathology
Mice, Inbred C57BL
Endoplasmic Reticulum Stress drug effects
Endothelial Cells metabolism
Endothelial Cells pathology
Human Umbilical Vein Endothelial Cells metabolism
MAP Kinase Signaling System drug effects
Connective Tissue Growth Factor metabolism
Connective Tissue Growth Factor genetics
Activating Transcription Factor 6 metabolism
Activating Transcription Factor 6 genetics
Reperfusion Injury metabolism
Reperfusion Injury pathology
Liver metabolism
Liver pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1879-260X
- Volume :
- 1870
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta. Molecular basis of disease
- Publication Type :
- Academic Journal
- Accession number :
- 39236363
- Full Text :
- https://doi.org/10.1016/j.bbadis.2024.167490