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
DNA material pCMFlag_hsESRRA (RDB06260)