Target validation in hypoxia-induced vascular remodeling using transcriptome/metabolome analysis.
The present study describes combined transcriptome and metabolome analysis for therapeutic target validation in hypoxia-induced vascular remodeling. Exposure to hypoxic conditions resulted in the upregulation of S100C mRNA and increased taurine (2-aminoethanesulfonic acid) content in the rat lung, as demonstrated by differential display and amino-acid content analysis. Hypoxia resulted in transcriptional activation of the S100C promoter through hypoxia-inducible factor-1 (HIF-1). Taurine suppressed HIF-1-mediated increases in S100C transcription. Moreover, oral taurine administration attenuated vascular remodeling in hypoxic rat lung, whereas depletion of endogenous taurine by administration of beta-alanine resulted in increased vascular remodeling. Inhibition of HIF transcription by taurine may be of therapeutic benefit in preventing hypoxia-induced vascular remodeling. In conclusion, we used transcriptome and metabolome analysis to identify a therapeutic low-molecular-weight ligand that plays a critical role in hypoxia-induced vascular remodeling. These techniques provided an excellent strategy for screening and validation of targets.
Amano
H
H
Department of Molecular and Cellular Pharmacology, Mie University School of Medicine, Tsu, Mie, Japan.
Maruyama
K
K
Naka
M
M
Tanaka
T
T
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D020869:Gene Expression Profiling / Q000379:methods*; D018390:Gene Targeting / Q000379:methods; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D009418:S100 Proteins / Q000096:biosynthesis / Q000235:genetics*; D013654:Taurine / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D014158:Transcription, Genetic
D009418:S100 Proteins; C072337:S100A11 protein, human; D013654:Taurine