Sirtuin 3 Therapy Attenuates Aging Expression, Oxidative Stress Parameters, and Neointimal Hyperplasia Formation in Vein Grafts

Abstract

Vein graft (VG) failure due to neointimal hyperplasia remains an important and unresolved problem in cardiovascular surgery. Sirtuin3 (SIRT3) is associated with oxidative stress and lifespan. We aimed to measure SIRT3 expression in the veins of humans and rats during aging, explore the inhibitory effects of SIRT3 on vascular smooth muscle cell (VSMC) proliferation and neointimal hyperplasia in VGs, and investigate the underlying mechanisms. SIRT3 mRNA and protein levels in saphenous veins of young and older humans and in veins of young and old rats were measured by quantitative real-time polymerized chain reaction (PCR) and Western blot analysis. Young and old male rats were randomized to the control (control), graft (graft), adenovirus-encoding green fluorescent protein (Ad-GFP), and adenovirus encoding SIRT3 (Ad-SIRT3) groups. At 7days after operation, the mRNA and protein levels of SIRT3 and endothelial nitric oxide synthase (eNOS) were measured by quantitative real-time PCR and Western blot analysis. The mRNA levels and enzyme activity of manganese superoxide dismutase (MnSOD) and catalase (CAT) were measured by quantitative real-time PCR and enzymatic activity assay kits, and total nitric oxide (NO) levels were measured by biochemical assay kits. Histomorphometric analysis of VGs and immunohistochemical staining for proliferative activity were performed at 4weeks after operation. The hemodynamic parameters of the VGs were also measured by ultrasonic examination. SIRT3 mRNA and protein levels were lower in older human and rat veins than in younger human and rat veins. Ad-SIRT3 treatment significantly increased the expression and concentration of SIRT3, MnSOD, CAT, eNOS, and NO in VGs at 7days after operation. Ad-SIRT3 gene transfer reduced the neointimal thickness and neointimal area/media area ratio in the VGs of the Ad-SIRT3 groups compared with the graft and Ad-GFP groups, especially in old rats. Proliferative activity was lower in the Ad-SIRT3 groups than in the other groups. The hemodynamic parameters of VGs were obviously improved in the Ad-SIRT3 groups. SIRT3 expression decreases in the veins of humans and rats during aging. Furthermore, SIRT3 overexpression can significantly reduce VSMC proliferation and neointimal hyperplasia in VGs. Local intravenous delivery of adenovirus encoding SIRT3 may be a promising gene therapy for preventing VG failure.