"Hypoxia-induced down-regulation of microRNA-449a/b impairs control over targeted SERPINE1 (PAI-1) mRNA - a mechanism involved in SERPINE1 (PAI-1) overexpression".
BACKGROUND
In damaged organs tissue repair and replacement of cells by connective tissue provokes a response of fibroblasts to cellular stress factors such as hypoxia.MicroRNAs (miRNA) are small non-coding RNA molecules which bind to their mRNA targets which eventually lead to repression of translation. Whether the response of fibroblasts to stress factors also involves the miRNA system is largely unknown.


RESULTS
By miRNA profiling we identified down-regulation of miRNA-449a/b expression in hypoxic fibroblasts. Specific miRNA inhibitors and mimics showed direct evidence for targeting the serine protease inhibitor (serpin) protein (SERPINE1; plasminogen activator inhibitor-1, PAI-1) by miRNA-449a/b leading to SERPINE1 mRNA and protein up- and down-regulation, respectively. SERPINE1 expression in vivo could be located predominantly in areas of fibrosis and remodeling.


CONCLUSIONS
Our study offers serious lines of evidence for a novel hypoxia-dependent mechanism involving hypoxia-induced decrease of clustered miRNA-449a/b, hypoxia-induced amplification of concomitant increase of targeted SERPINE1 (PAI-1) and its overexpression in tissues showing a hypoxic environment.
Muth
Michaela
M
Institute of Pathology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
Theophile
Katharina
K
Hussein
Kais
K
Jacobi
Christoph
C
Kreipe
Hans
H
Bock
Oliver
O
D000293:Adolescent; D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D020869:Gene Expression Profiling; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D016030:Kidney Transplantation; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D046228:Microarray Analysis; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D014184:Transplantation, Homologous / Q000473:pathology
C544530:MIRN449 microRNA, human; D035683:MicroRNAs; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger