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miR-146a targets Fos expression in human cardiac cells.

Palomer X, Capdevila-Busquets E, Botteri G, Davidson MM, Rodríguez C, Martínez-González J, Vidal F, Barroso E, Chan TO, Feldman AM, Vázquez-Carrera M - Dis Model Mech (2015)

Bottom Line: These changes correlated with a diminution in the DNA-binding activity of AP-1, the Fos-containing transcription factor complex.The specific regulation of this MMP by miR-146a was further confirmed at the secretion and enzymatic activity levels, as well as after anti-miR-mediated miR-146a inhibition.The results reported here demonstrate that Fos is a direct target of miR-146a activity and that downregulation of the Fos-AP-1 pathway by miR-146a has the capacity to inhibit MMP-9 activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Therapeutic Chemistry, IBUB (Institut de Biomedicina de la Universitat de Barcelona) and CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Faculty of Pharmacy, University of Barcelona, Diagonal 643, Barcelona E-08028, Spain.

No MeSH data available.


Related in: MedlinePlus

Schematic model depicting the potential role of miR-146a in TNF-α-induced effects in the heart. Exposure of cardiac cells to TNF-α strongly induces miR-146a, probably in a process dependent on NF-κB transcriptional activity (dashed arrow). Enhanced miR-146a levels are directly responsible for Fos expression downregulation. The subsequent reduction in AP-1 DNA-binding activity results in the modulation of inflammation by attenuating IL-6 and MCP-1 expression, together with a reduction in MMP-9 expression and activity. AP-1, activator protein-1; Fos, FBJ murine osteosarcoma viral oncogene homolog; IL-6, interleukin 6; MCP-1, monocyte chemoattractant protein 1; MMP-9, matrix metalloproteinase 9; NF-κB, nuclear factor-κB; TNF-α, tumor necrosis factor α.
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DMM020768F6: Schematic model depicting the potential role of miR-146a in TNF-α-induced effects in the heart. Exposure of cardiac cells to TNF-α strongly induces miR-146a, probably in a process dependent on NF-κB transcriptional activity (dashed arrow). Enhanced miR-146a levels are directly responsible for Fos expression downregulation. The subsequent reduction in AP-1 DNA-binding activity results in the modulation of inflammation by attenuating IL-6 and MCP-1 expression, together with a reduction in MMP-9 expression and activity. AP-1, activator protein-1; Fos, FBJ murine osteosarcoma viral oncogene homolog; IL-6, interleukin 6; MCP-1, monocyte chemoattractant protein 1; MMP-9, matrix metalloproteinase 9; NF-κB, nuclear factor-κB; TNF-α, tumor necrosis factor α.

Mentions: In summary, the results reported here demonstrate that Fos is a direct target of miR-146a activity and that downregulation of the Fos–AP-1 pathway by miR-146a can inhibit MMP-9 activity (Fig. 6). Fos is one of the immediate early genes whose expression is boosted during ischemic injury, heart failure and cardiomyopathy. Likewise, it has been reported that Fos gene expression is stimulated as a result of insulin insufficiency in the diabetic myocardium (Wang et al., 1999) and also in the adipose tissue of streptozotocin-induced diabetic rats (Olson and Pessin, 1994). In fact, the transcriptional activity of AP-1 is among the most robustly enhanced of 54 transcription factors examined in the failing heart (Freire et al., 2007). In order to prevent the pathological effects caused by its dysfunction, regulation of AP-1 is complex and occurs at multiple interwoven transcriptional and post-transcriptional levels. This includes transcription of its subunits, mRNA translation and turnover, protein stability and activity, subcellular localization, and interaction with other transcription factors and cofactors (Schonthaler et al., 2011). Here, we demonstrate that miR-146a might post-transcriptionally regulate Fos levels and, consequently, AP-1 activity as well. Furthermore, the results presented here are very appealing because numerous studies have shown that upregulation of MMP-2 and MMP-9 expression correlates fairly well with heart failure, whereas their inhibition suppresses ventricular remodeling, myocardial dysfunction and development of heart failure (Meiners et al., 2004). In recent years, the development of antisense-oligonucleotide-mediated (anti-miR) knockdown and miRNA overexpression techniques has become a very attractive pharmacological target in the treatment of cardiovascular disease. In this respect, miR-146a emerges as a new and promising therapeutic tool for preventing cardiac disorders associated with inflammatory states in the heart.Fig. 6.


miR-146a targets Fos expression in human cardiac cells.

Palomer X, Capdevila-Busquets E, Botteri G, Davidson MM, Rodríguez C, Martínez-González J, Vidal F, Barroso E, Chan TO, Feldman AM, Vázquez-Carrera M - Dis Model Mech (2015)

Schematic model depicting the potential role of miR-146a in TNF-α-induced effects in the heart. Exposure of cardiac cells to TNF-α strongly induces miR-146a, probably in a process dependent on NF-κB transcriptional activity (dashed arrow). Enhanced miR-146a levels are directly responsible for Fos expression downregulation. The subsequent reduction in AP-1 DNA-binding activity results in the modulation of inflammation by attenuating IL-6 and MCP-1 expression, together with a reduction in MMP-9 expression and activity. AP-1, activator protein-1; Fos, FBJ murine osteosarcoma viral oncogene homolog; IL-6, interleukin 6; MCP-1, monocyte chemoattractant protein 1; MMP-9, matrix metalloproteinase 9; NF-κB, nuclear factor-κB; TNF-α, tumor necrosis factor α.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4582106&req=5

DMM020768F6: Schematic model depicting the potential role of miR-146a in TNF-α-induced effects in the heart. Exposure of cardiac cells to TNF-α strongly induces miR-146a, probably in a process dependent on NF-κB transcriptional activity (dashed arrow). Enhanced miR-146a levels are directly responsible for Fos expression downregulation. The subsequent reduction in AP-1 DNA-binding activity results in the modulation of inflammation by attenuating IL-6 and MCP-1 expression, together with a reduction in MMP-9 expression and activity. AP-1, activator protein-1; Fos, FBJ murine osteosarcoma viral oncogene homolog; IL-6, interleukin 6; MCP-1, monocyte chemoattractant protein 1; MMP-9, matrix metalloproteinase 9; NF-κB, nuclear factor-κB; TNF-α, tumor necrosis factor α.
Mentions: In summary, the results reported here demonstrate that Fos is a direct target of miR-146a activity and that downregulation of the Fos–AP-1 pathway by miR-146a can inhibit MMP-9 activity (Fig. 6). Fos is one of the immediate early genes whose expression is boosted during ischemic injury, heart failure and cardiomyopathy. Likewise, it has been reported that Fos gene expression is stimulated as a result of insulin insufficiency in the diabetic myocardium (Wang et al., 1999) and also in the adipose tissue of streptozotocin-induced diabetic rats (Olson and Pessin, 1994). In fact, the transcriptional activity of AP-1 is among the most robustly enhanced of 54 transcription factors examined in the failing heart (Freire et al., 2007). In order to prevent the pathological effects caused by its dysfunction, regulation of AP-1 is complex and occurs at multiple interwoven transcriptional and post-transcriptional levels. This includes transcription of its subunits, mRNA translation and turnover, protein stability and activity, subcellular localization, and interaction with other transcription factors and cofactors (Schonthaler et al., 2011). Here, we demonstrate that miR-146a might post-transcriptionally regulate Fos levels and, consequently, AP-1 activity as well. Furthermore, the results presented here are very appealing because numerous studies have shown that upregulation of MMP-2 and MMP-9 expression correlates fairly well with heart failure, whereas their inhibition suppresses ventricular remodeling, myocardial dysfunction and development of heart failure (Meiners et al., 2004). In recent years, the development of antisense-oligonucleotide-mediated (anti-miR) knockdown and miRNA overexpression techniques has become a very attractive pharmacological target in the treatment of cardiovascular disease. In this respect, miR-146a emerges as a new and promising therapeutic tool for preventing cardiac disorders associated with inflammatory states in the heart.Fig. 6.

Bottom Line: These changes correlated with a diminution in the DNA-binding activity of AP-1, the Fos-containing transcription factor complex.The specific regulation of this MMP by miR-146a was further confirmed at the secretion and enzymatic activity levels, as well as after anti-miR-mediated miR-146a inhibition.The results reported here demonstrate that Fos is a direct target of miR-146a activity and that downregulation of the Fos-AP-1 pathway by miR-146a has the capacity to inhibit MMP-9 activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Therapeutic Chemistry, IBUB (Institut de Biomedicina de la Universitat de Barcelona) and CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Faculty of Pharmacy, University of Barcelona, Diagonal 643, Barcelona E-08028, Spain.

No MeSH data available.


Related in: MedlinePlus