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miRNA-21 is dysregulated in response to vein grafting in multiple models and genetic ablation in mice attenuates neointima formation.

McDonald RA, White KM, Wu J, Cooley BC, Robertson KE, Halliday CA, McClure JD, Francis S, Lu R, Kennedy S, George SJ, Wan S, van Rooij E, Baker AH - Eur. Heart J. (2013)

Bottom Line: Identifying novel strategies to prevent neointimal thickening is important.Thus, this study aimed to identify microRNAs (miRNAs) that are dysregulated during neointimal formation and determine their pathophysiological relevance following miRNA manipulation.Furthermore, pharmacological knockdown of miR-21 in human veins resulted in target gene de-repression and a significant reduction in neointimal formation.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, UK.

ABSTRACT

Aims: The long-term failure of autologous saphenous vein bypass grafts due to neointimal thickening is a major clinical burden. Identifying novel strategies to prevent neointimal thickening is important. Thus, this study aimed to identify microRNAs (miRNAs) that are dysregulated during neointimal formation and determine their pathophysiological relevance following miRNA manipulation.

Methods and results: We undertook a microarray approach to identify dysregulated miRNAs following engraftment in an interpositional porcine graft model. These profiling experiments identified a number of miRNAs which were dysregulated following engraftment. miR-21 levels were substantially elevated following engraftment and these results were confirmed by quantitative real-time PCR in mouse, pig, and human models of vein graft neointimal formation. Genetic ablation of miR-21 in mice or grafted veins dramatically reduced neointimal formation in a mouse model of vein grafting. Furthermore, pharmacological knockdown of miR-21 in human veins resulted in target gene de-repression and a significant reduction in neointimal formation.

Conclusion: This is the first report demonstrating that miR-21 plays a pathological role in vein graft failure. Furthermore, we also provided evidence that knockdown of miR-21 has therapeutic potential for the prevention of pathological vein graft remodelling.

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Related in: MedlinePlus

miR-21 expression in human vein subjected to culture. (A–D) In situ hybridization of miR-21 in human saphenous veins following 0, 4, 7, and 14 days of cell culture. (E–H) In situ hybridization on serial sections with a scrambled probe. (I–L) Serial sections stained with anti-α-actin antibodies (SMA) to determine smooth muscle cells. Scale bar represents 100 μm, applicable to all panels.
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EHT105F5: miR-21 expression in human vein subjected to culture. (A–D) In situ hybridization of miR-21 in human saphenous veins following 0, 4, 7, and 14 days of cell culture. (E–H) In situ hybridization on serial sections with a scrambled probe. (I–L) Serial sections stained with anti-α-actin antibodies (SMA) to determine smooth muscle cells. Scale bar represents 100 μm, applicable to all panels.

Mentions: In situ hybridization for miR-21 in surgically prepared HSV segments demonstrated that miR-21 was expressed in medial and neointimal SMCs (Figure 5). Immunohistochemistry in sequential serial sections demonstrated that miR-21 expression was localized in areas which stained positive for α-actin (Figure 5J–L).Figure 5


miRNA-21 is dysregulated in response to vein grafting in multiple models and genetic ablation in mice attenuates neointima formation.

McDonald RA, White KM, Wu J, Cooley BC, Robertson KE, Halliday CA, McClure JD, Francis S, Lu R, Kennedy S, George SJ, Wan S, van Rooij E, Baker AH - Eur. Heart J. (2013)

miR-21 expression in human vein subjected to culture. (A–D) In situ hybridization of miR-21 in human saphenous veins following 0, 4, 7, and 14 days of cell culture. (E–H) In situ hybridization on serial sections with a scrambled probe. (I–L) Serial sections stained with anti-α-actin antibodies (SMA) to determine smooth muscle cells. Scale bar represents 100 μm, applicable to all panels.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3675389&req=5

EHT105F5: miR-21 expression in human vein subjected to culture. (A–D) In situ hybridization of miR-21 in human saphenous veins following 0, 4, 7, and 14 days of cell culture. (E–H) In situ hybridization on serial sections with a scrambled probe. (I–L) Serial sections stained with anti-α-actin antibodies (SMA) to determine smooth muscle cells. Scale bar represents 100 μm, applicable to all panels.
Mentions: In situ hybridization for miR-21 in surgically prepared HSV segments demonstrated that miR-21 was expressed in medial and neointimal SMCs (Figure 5). Immunohistochemistry in sequential serial sections demonstrated that miR-21 expression was localized in areas which stained positive for α-actin (Figure 5J–L).Figure 5

Bottom Line: Identifying novel strategies to prevent neointimal thickening is important.Thus, this study aimed to identify microRNAs (miRNAs) that are dysregulated during neointimal formation and determine their pathophysiological relevance following miRNA manipulation.Furthermore, pharmacological knockdown of miR-21 in human veins resulted in target gene de-repression and a significant reduction in neointimal formation.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, UK.

ABSTRACT

Aims: The long-term failure of autologous saphenous vein bypass grafts due to neointimal thickening is a major clinical burden. Identifying novel strategies to prevent neointimal thickening is important. Thus, this study aimed to identify microRNAs (miRNAs) that are dysregulated during neointimal formation and determine their pathophysiological relevance following miRNA manipulation.

Methods and results: We undertook a microarray approach to identify dysregulated miRNAs following engraftment in an interpositional porcine graft model. These profiling experiments identified a number of miRNAs which were dysregulated following engraftment. miR-21 levels were substantially elevated following engraftment and these results were confirmed by quantitative real-time PCR in mouse, pig, and human models of vein graft neointimal formation. Genetic ablation of miR-21 in mice or grafted veins dramatically reduced neointimal formation in a mouse model of vein grafting. Furthermore, pharmacological knockdown of miR-21 in human veins resulted in target gene de-repression and a significant reduction in neointimal formation.

Conclusion: This is the first report demonstrating that miR-21 plays a pathological role in vein graft failure. Furthermore, we also provided evidence that knockdown of miR-21 has therapeutic potential for the prevention of pathological vein graft remodelling.

Show MeSH
Related in: MedlinePlus