| RRC ID |
36049
|
| Author |
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.
|
| Title |
A key role of PGC-1α transcriptional coactivator in production of VEGF by a novel angiogenic agent COA-Cl in cultured human fibroblasts.
|
| Journal |
Physiol Rep
|
| Abstract |
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.
|
| Volume |
4(6)
|
| Published |
2016-3-1
|
| DOI |
10.14814/phy2.12742
|
| PII |
4/6/e12742
|
| PMID |
27033444
|
| PMC |
PMC4814893
|
| MeSH |
Adenosine / analogs & derivatives*
Adenosine / pharmacology
Angiogenesis Inducing Agents / pharmacology*
Animals
COS Cells
Chlorocebus aethiops
Dose-Response Relationship, Drug
Fibroblasts / drug effects*
Fibroblasts / metabolism
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
RNA Interference
RNA, Messenger / metabolism
Receptors, Estrogen / genetics
Receptors, Estrogen / metabolism
Signal Transduction / drug effects
Time Factors
Transcription Factors / genetics
Transcription Factors / metabolism*
Transcription, Genetic
Transcriptional Activation
Transfection
Up-Regulation
Vascular Endothelial Growth Factor A / genetics
Vascular Endothelial Growth Factor A / metabolism*
|
| Times Cited |
6
|
| Resource |
| DNA material |
pCMFlag_hsESRRA (RDB06260) |
