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A key role of PGC-1 α transcriptional coactivator in production of VEGF by a novel angiogenic agent COA-Cl in cultured human fibroblasts
Open accessAbstract
We previously demonstrated a potent angiogenic effect of a newly developed adenosine-like agent namedCOA-Cl.COA-Cl exerted tube forming activity in human umbilical vein endothelial cells in the presence of normal human dermal fibroblasts (NHDF). We therefore explored whether and howCOA-Cl modulates gene expression and protein secretion ofVEGF, a master regulator of angiogenesis, inNHDFRT-PCRandELISArevealed thatCOA-Cl upregulatedVEGF mRNAexpression and protein secretion inNHDFHIF1α(hypoxia-inducible factor 1α), a transcription factor, andPGC-1α(peroxisome proliferator-activated receptor-γcoactivator-1α), a transcriptional coactivator, are known to positively regulate theVEGFgene. Immunoblot andRT-PCRanalyses revealed thatCOA-Cl markedly upregulated the expression ofPGC-1αprotein andmRNACOA-Cl had no effect on the expression ofHIF1αprotein andmRNAin both hypoxia and normoxia. SilencingPGC-1αgene, but notHIF1αgene, by small interferingRNAattenuated the ability ofCOA-Cl to promoteVEGFsecretion. When an N-terminal fragment ofPGC-1αwas cotransfected with its partner transcription factorERRα(estrogen-related receptor-α) inCOS-7 cells,COA-Cl upregulated the expression of the endogenousVEGF mRNA However,COA-Cl had no effect on the expression ofVEGF, whenHIF1αwas transfected.COA-Cl inducesVEGFgene expression and protein secretion in fibroblasts. The transcriptional coactivatorPGC-1α, in concert withERRα, plays a key role in theCOA-Cl-inducedVEGFproduction.COA-Cl-induced activation ofPGC-1α-ERRα-VEGFpathway has a potential as a novel means for therapeutic angiogenesis.
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In the middle cerebral artery occlusion model, delayed administration of Mexidol 6 h after ischemia induction and for 6 subsequent days resulted in a 30% decrease in brain damage.
“In the middle cerebral artery occlusion model, the delayed administration of Mexidol 6 h after ischemia induction and for 6 subsequent days resulted in a 30% decrease in brain damage [88].”
From Protective Effects of PGC-1α Activators on Ischemic Stroke in a Rat Model of Photochemically Induced Thrombosis (2021) · cites this paper as [88]
The Materials and Methods section describes COA-Cl treatment of cultured human fibroblasts, and the Results report VEGF expression rather than brain injury. Searches for Mexidol, middle cerebral artery occlusion, delayed dosing, and a 30% reduction found no passage addressing the cited claim. The indexed passages provide no page numbers. (LLM, conf=0.76)
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References 31 · Cited by 13
Research works printed but not linked: 29
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Metadata
- Authors
- Igarashi, J., Okamoto, R., Yamashita, T., Hashimoto, T., Karita, S., Nakai, K., Kubota, Y., Takata, M., Yamaguchi, F., Tokuda, M., Sakakibara, N., Tsukamoto, I., Konishi, R., & Hirano, K.
- Affiliations
- Kagawa University (JP)
- Tokushima Bunri University (JP)
- Corresponding author
- Igarashi, Junsuke
- ORCID
- Venue
- Physiological Reports
- Publisher
- Wiley
- Published
- 2016-03
- Volume
- 4
- Issue
- 6
- Pages
- e12742
- ISSN
- 2051-817X (ISSN-L)
- PMC
- PMC4814893
- OpenAlex
- W2318243652
- Cited by
- 13
- References
- 31
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 2 · 2021: 1 · 2020: 2 · 2019: 3 · 2017: 2 · 2016: 1
- FWCI
- 1.04
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Physiological Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Grants-in-Aid for Scientific Research (25461132, 24591654)
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- PGC-1α, vascular endothelial growth factor, angiogenesis, therapeutic angiogenesis, estrogen-related receptor alpha, HIF-1α, dermal fibroblasts, VEGF expression, transcriptional coactivator, endothelial tube formation
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, ERRalpha Estrogen-Related Receptor, Adenosine, Animals, Chlorocebus aethiops, Dose-Response Relationship, Drug, Fibroblasts, Humans, Receptors, Estrogen, RNA, Messenger, Time Factors, Transcription Factors, Transcription, Genetic, Transfection, Signal Transduction, Transcriptional Activation, Up-Regulation, COS Cells, RNA Interference, Vascular Endothelial Growth Factor A, Angiogenesis Inducing Agents, Hypoxia-Inducible Factor 1, alpha Subunit
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