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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.We undertook a microarray approach to identify dysregulated miRNAs following engraftment in an interpositional porcine graft model.

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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Effect of miR-21 ablation on neointimal formation in a mouse model of vein grafting. (A) The neointimal area 28 days post-grafting in wild-type mice, miR-21 knockouts, and miR-21 knockout veins engrafted into wild-type mice. (B) Vessel wall thickness in grafts from wild-type and knockout mice at 0 and 28 days; sections are stained with elastin van Gieson. Arrows indicate the neointimal layer. n = 5–10, ***P < 0.001 vs. wild-type. Scale bar represents 200 μm, applicable to all panels.
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EHT105F6: Effect of miR-21 ablation on neointimal formation in a mouse model of vein grafting. (A) The neointimal area 28 days post-grafting in wild-type mice, miR-21 knockouts, and miR-21 knockout veins engrafted into wild-type mice. (B) Vessel wall thickness in grafts from wild-type and knockout mice at 0 and 28 days; sections are stained with elastin van Gieson. Arrows indicate the neointimal layer. n = 5–10, ***P < 0.001 vs. wild-type. Scale bar represents 200 μm, applicable to all panels.

Mentions: In order to address whether the elevation of miR-21 plays an important role in the development of vein graft neointimal formation, we performed isogenic vein grafting in miR-21 knockout mice and wild-type controls. At 28 days post-engraftment, the neointimal area was dramatically reduced by 81% in miR-21 knockout mice compared with wild-type controls (P < 0.001, n = 7–10/group) (Figure 6A and B). Additionally, neointimal lesions in miR-21 knockout mice had significantly lower SMC content than controls (see Supplementary material online, Figure S3).Figure 6


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)

Effect of miR-21 ablation on neointimal formation in a mouse model of vein grafting. (A) The neointimal area 28 days post-grafting in wild-type mice, miR-21 knockouts, and miR-21 knockout veins engrafted into wild-type mice. (B) Vessel wall thickness in grafts from wild-type and knockout mice at 0 and 28 days; sections are stained with elastin van Gieson. Arrows indicate the neointimal layer. n = 5–10, ***P < 0.001 vs. wild-type. Scale bar represents 200 μm, applicable to all panels.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

EHT105F6: Effect of miR-21 ablation on neointimal formation in a mouse model of vein grafting. (A) The neointimal area 28 days post-grafting in wild-type mice, miR-21 knockouts, and miR-21 knockout veins engrafted into wild-type mice. (B) Vessel wall thickness in grafts from wild-type and knockout mice at 0 and 28 days; sections are stained with elastin van Gieson. Arrows indicate the neointimal layer. n = 5–10, ***P < 0.001 vs. wild-type. Scale bar represents 200 μm, applicable to all panels.
Mentions: In order to address whether the elevation of miR-21 plays an important role in the development of vein graft neointimal formation, we performed isogenic vein grafting in miR-21 knockout mice and wild-type controls. At 28 days post-engraftment, the neointimal area was dramatically reduced by 81% in miR-21 knockout mice compared with wild-type controls (P < 0.001, n = 7–10/group) (Figure 6A and B). Additionally, neointimal lesions in miR-21 knockout mice had significantly lower SMC content than controls (see Supplementary material online, Figure S3).Figure 6

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.We undertook a microarray approach to identify dysregulated miRNAs following engraftment in an interpositional porcine graft model.

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