Dedicator of cytokinesis 2 silencing therapy inhibits neointima formation and improves blood flow in rat vein grafts

• Published in: Journal of molecular and cellular cardiology 2019-03, Vol.128, p.134-144
• Main Authors: Cao, Bo-Jun, Wang, Xiao-Wen, Zhu, Lei, Zou, Rong-Jiang, Lu, Zhi-Qian
• Format: Article
• Language: English
• Subjects: Dedicator of cytokinesis 2; Gene therapy; Neointima formation; Vein graft failure
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2019.01.030

The high rate of vein graft failure due to neointimal hyperplasia is a major challenge for cardiovascular surgery. Finding novel approaches to prevent neointimal hyperplasia is important. Thus, the purpose of this study was to investigate whether dedicator of cytokinesis 2 (DOCK2) plays a role in the development of neointima formation in the vein grafts. We found that DOCK2 levels were significantly elevated in the vein grafts following grafting surgery. In addition, overexpression of DOCK2 promoted venous smooth muscle cell (SMC) proliferation and migration. Conversely, knocking-down endogenous DOCK2 expression in venous SMCs inhibited SMC proliferation and migration. Consistent with this, knocking-down DOCK2 expression in the grafted veins significantly reduced neointimal formation compared with the controls 28 days after vein transplantation. Moreover, DOCK2 silencing treatment improved hemodynamics in the vein grafts. Mechanistically, knockdown of DOCK2 significantly alleviated the vein graft-induced down regulation of SMC contractile protein expression and impeded the vein graft-induction of both Cyclin D1 and PCNA expression. In particular, to ensure high efficiency when transferring the DOCK2 short hairpin RNA (shDOCK2) into the grafted veins, a 30% poloxamer F-127 gel incorporated with 0.25% trypsin was smeared around the vein grafts to increase the adenovirus contact time and penetration. DOCK2 silencing gene therapy effectively attenuates neointimal hyperplasia in vein grafts. Knock-down of DOCK2 would be a potential therapeutic approach for the treatment of vein graft failure. •DOCK2 is markedly up-regulated in the neointimal layer of vein grafts following grafting surgery.•Knock-down of DOCK2 inhibits venous SMC proliferation and migration in vitro.•DOCK2 silencing therapy attenuates vein graft neointimal formation and improves the hemodynamics of the vein grafts.•Knock-down of DOCK2 significantly alleviates the vein graft-induced down regulation of SMC contractile protein expression.•Knock-down of DOCK2 impedes the expression of cyclin D1 induced by vein grafting.