Osteopontin is indispensible for AP1-mediated angiotensin II-related miR-21 transcription during cardiac fibrosis

Osteopontin (OPN) is a multifunctional cytokine critically involved in cardiac fibrosis. However, the underlying mechanisms are unresolved. Non-coding RNAs are powerful regulators of gene expression and thus might mediate this process. OPN and miR-21 were significantly increased in cardiac biopsies...

Celý popis

Uložené v:
Podrobná bibliografia
Vydané v:European heart journal Ročník 36; číslo 32; s. 2184
Hlavní autori: Lorenzen, Johan M, Schauerte, Celina, Hübner, Anika, Kölling, Malte, Martino, Filippo, Scherf, Kristian, Batkai, Sandor, Zimmer, Karina, Foinquinos, Ariana, Kaucsar, Tamas, Fiedler, Jan, Kumarswamy, Regalla, Bang, Claudia, Hartmann, Dorothee, Gupta, Shashi K, Kielstein, Jan, Jungmann, Andreas, Katus, Hugo A, Weidemann, Frank, Müller, Oliver J, Haller, Hermann, Thum, Thomas
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: England 21.08.2015
Predmet:
Adenoviridae
Aged
Angiotensin II - physiology
Animals
Cell Survival
Cells, Cultured
Collagen - metabolism
Female
Fibrosis - genetics
Gene Silencing
Genetic Vectors - administration & dosage
Humans
In Vitro Techniques
Male
Mice, Knockout
MicroRNAs - genetics
MicroRNAs - metabolism
Myocardium - pathology
Myofibroblasts - physiology
Osteopontin - pharmacology
Osteopontin - physiology
Phosphatidylinositol 3-Kinases - metabolism
PTEN Phosphohydrolase - metabolism
Recombinant Proteins - pharmacology
Transcription Factors
Osteopontin
Cardiac fibrosis
microRNA
miR-21
Angiotensin II
ISSN:1522-9645, 1522-9645
On-line prístup:Zistit podrobnosti o prístupe
Tagy: Pridať tag
Žiadne tagy, Buďte prvý, kto otaguje tento záznam!
Popis
Shrnutí:Osteopontin (OPN) is a multifunctional cytokine critically involved in cardiac fibrosis. However, the underlying mechanisms are unresolved. Non-coding RNAs are powerful regulators of gene expression and thus might mediate this process. OPN and miR-21 were significantly increased in cardiac biopsies of patients with myocardial fibrosis. Ang II infusion via osmotic minipumps led to specific miRNA regulations with miR-21 being strongly induced in wild-type (WT) but not OPN knockout (KO) mice. This was associated with enhanced cardiac collagen content, myofibroblast activation, ERK-MAP kinase as well as AKT signalling pathway activation and a reduced expression of Phosphatase and Tensin Homologue (PTEN) as well as SMAD7 in WT but not OPN KO mice. In contrast, cardiotropic AAV9-mediated overexpression of OPN in vivo further enhanced cardiac fibrosis. In vitro, Ang II induced expression of miR-21 in WT cardiac fibroblasts, while miR-21 levels were unchanged in OPN KO fibroblasts. As pri-miR-21 was also increased by Ang II, we studied potential involved upstream regulators; Electrophoretic Mobility Shift and Chromatin Immunoprecipitation analyses confirmed activation of the miR-21 upstream-transcription factor AP-1 by Ang II. Recombinant OPN directly activated miR-21, enhanced fibrosis, and activated the phosphoinositide 3-kinase pathway. Locked nucleic acid-mediated miR-21 silencing ameliorated cardiac fibrosis development in vivo. In cardiac fibrosis related to Ang II, miR-21 is transcriptionally activated and targets PTEN/SMAD7 resulting in increased fibroblast survival. OPN KO animals are protected from miR-21 increase and fibrosis development due to impaired AP-1 activation and fibroblast activation.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1522-9645
1522-9645
DOI:10.1093/eurheartj/ehv109