Dedicator of cytokinesis 2 silencing therapy inhibits neointima formation and improves blood flow in rat vein grafts
| Autor: | Xiao-Wen Wang, Zhiqian Lu, Rong-Jiang Zou, Lei Zhu, Bo-Jun Cao |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Graft Rejection
0301 basic medicine Neointima Myocytes Smooth Muscle Cell Transplants Poloxamer 030204 cardiovascular system & hematology Veins Small hairpin RNA 03 medical and health sciences 0302 clinical medicine Cyclin D1 Downregulation and upregulation Proliferating Cell Nuclear Antigen Animals Guanine Nucleotide Exchange Factors Humans Medicine Gene silencing Molecular Biology Neointimal hyperplasia Gene knockdown Hyperplasia business.industry Cardiovascular Surgical Procedures Gene Expression Regulation Developmental medicine.disease Rats surgical procedures operative 030104 developmental biology medicine.anatomical_structure cardiovascular system Cancer research Cardiology and Cardiovascular Medicine business |
| Zdroj: | Journal of Molecular and Cellular Cardiology. 128:134-144 |
| ISSN: | 0022-2828 |
| DOI: | 10.1016/j.yjmcc.2019.01.030 |
| Popis: | Objective 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. Methods and results 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. Conclusions 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. |
| Databáze: | OpenAIRE |
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