Abstract
Neointima formation is the major reason for vein graft failure. However, the underlying mechanism is unclear. The aim of this study was to determine the role of miR-26a in the development of neointimal hyperplasia of autogenous vein grafts. Using autologous jugular vein grafts in the rat carotid artery as a model, we found that miR-26a was significantly downregulated in grafted veins as well as proliferating vascular smooth muscle cells (VSMCs) stimulated with platelet-derived growth factor-BB (PDGF-BB). Overexpression of miR-26a reduced the proliferation and migration of VSMCs. Further analysis revealed that the effects of miR-26a in VSMCs were mediated by targeting MAPK6 at the mRNA and protein levels. Luciferase assays showed that miR-26a repressed wild type (WT) MAPK6-3′-UTR-luciferase activity but not mutant MAPK6-3′-UTR-luciferease reporter. MAPK6 deficiency reduced proliferation and migration; in contrast, overexpression of MAPK6 enhanced the proliferation and migration of VSMCs. This study confirmed that neointimal hyperplasia in vein grafts was reduced in vivo by up-regulated miR-26a expression. In conclusion, our results showed that miR-26a is an important regulator of VSMC functions and neointimal hyperplasia, suggesting that miR-26a may be a potential therapeutic target for autologous vein graft diseases.
Highlights
Neointima formation is the major reason for vein graft failure
To investigate whether miR-26a is a critical regulator for vascular smooth muscle cells (VSMCs) proliferation in the neointima, we used a well-established model of rat autologous jugular vein grafts
We found that miR-26a expression in VSMCs was significantly down-regulated after treatment with platelet-derived growth factor-BB (PDGF-BB) in a dose-dependent and time-dependent manner (Fig. 1C and D)
Summary
Neointima formation is the major reason for vein graft failure. the underlying mechanism is unclear. Our results showed that miR-26a is an important regulator of VSMC functions and neointimal hyperplasia, suggesting that miR-26a may be a potential therapeutic target for autologous vein graft diseases. A major cause of vein graft failure is intimal hyperplasia, which predominantly results from proliferation and migration of vascular smooth muscle cells (VSMCs) and the deposition of extracellular matrix[5]. MiR-26a up-regulation in ASMCsDes−/− induced hypertrophy via suppression of the anti-hypertrophic protein GSK-3β21 It remains unclear whether miR-26a regulates the function of rat jugular vein smooth muscle cells, which are associated with neointimal formation resulting from vein graft failure. We report that miR-26a is an important regulator of VSMC functions and neointimal hyperplasia by targeting MAPK6 at the gene level. Our study provides a better understanding of neointimal formation associated with vein graft failure
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