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- Title
Simvastatin reduces venous stenosis formation in a murine hemodialysis vascular access model.
- Authors
Janardhanan, Rajiv; Yang, Binxia; Vohra, Pawan; Roy, Bhaskar; Withers, Sarah; Bhattacharya, Santanu; Mandrekar, Jaywant; Kong, Hyunjoon; Leof, Edward B; Mukhopadhyay, Debabrata; Misra, Sanjay
- Abstract
Venous neointimal hyperplasia (VNH) is responsible for hemodialysis vascular access malfunction. Here we tested whether VNH formation occurs, in part, due to vascular endothelial growth factor-A (VEGF-A) and matrix metalloproteinase (MMP)-9 gene expression causing adventitial fibroblast transdifferentiation to myofibroblasts (α-SMA-positive cells). These cells have increased proliferative and migratory capacity leading to VNH formation. Simvastatin was used to decrease VEGF-A and MMP-9 gene expression in our murine arteriovenous fistula model created by connecting the right carotid artery to the ipsilateral jugular vein. Compared to fistulae of vehicle-treated mice, the fistulae of simvastatin-treated mice had the expected decrease in VEGF-A and MMP-9 but also showed a significant reduction in MMP-2 expression with a significant decrease in VNH and a significant increase in the mean lumen vessel area. There was an increase in terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, and decreases in α-SMA density, cell proliferation, and HIF-1α and hypoxyprobe staining. This latter result prompted us to determine the effect of simvastatin on fibroblasts subjected to hypoxia in vitro. Simvastatin-treated fibroblasts had a significant decrease in myofibroblast production along with decreased cellular proliferation, migration, and MMP-9 activity but increased caspase 3 activity suggesting increased apoptosis. Thus, simvastatin results in a significant reduction in VNH, with increase in mean lumen vessel area by decreasing VEGF-A/MMP-9 pathway activity.
- Subjects
SIMVASTATIN; STENOSIS; ARTERIOVENOUS fistula; SURGICAL arteriovenous shunts; CHRONIC kidney failure; CORONARY restenosis; VASCULAR endothelial growth factors; HEMODIALYSIS patients; PREVENTION
- Publication
Kidney International, 2013, Vol 84, Issue 2, p338
- ISSN
0085-2538
- Publication type
Article
- DOI
10.1038/ki.2013.112