Role of Girdin in intimal hyperplasia in vein grafts and efficacy of atelocollagen-mediated application of small interfering RNA for vein graft failure.
OBJECTIVE
Intimal hyperplasia is a major obstacle to patency in grafted veins. Although migration and proliferation of vascular smooth muscle cells (SMCs) pivotally affect the vascular remodeling process, no therapy has been established to prevent intimal hyperplasia of vein grafts. We previously reported that the actin-binding protein Girdin crucially affects arterial remodeling. In this study, we investigated the role of Girdin in venous SMCs and evaluated a therapeutic strategy for vein graft failure in vivo using small interfering RNA (siRNA) that targets Girdin.


METHODS
We investigated the relationship between Girdin expression and intimal hyperplasia using a rabbit vein graft model. Vein grafts under low-flow conditions were performed in Japanese White rabbits. For in vitro analyses, we isolated primary venous SMCs from vein graft neointima. siRNA that targets Girdin was mixed with atelocollagen, which stabilizes and releases nucleic acid reagents slowly and is applied perivascularly to the vein grafts at operation. Intimal hyperplasia was evaluated 4 weeks later.


RESULTS
In the rabbit model, increased Girdin expression was seen in the neointima after the grafting operation. Using primary venous SMCs, we showed that Girdin is required for rearrangement of the actin cytoskeleton in venous SMCs and that siRNA-mediated Girdin knockdown significantly reduced venous SMC migration and proliferation. Girdin knockdown via perivascular application of siRNA using atelocollagen markedly reduced intimal thickening after the grafting operation.


CONCLUSIONS
Depletion of Girdin attenuated venous SMCs migration and proliferation in vitro and intimal hyperplasia in vein grafts in vivo. Our findings suggest that Girdin affects migration and proliferation of vascular SMCs in vein grafts and that controlled release of Girdin siRNA using atelocollagen could be a novel therapeutic strategy for vein graft failure.
Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Division of Vascular Surgery, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Hiroki
H
Miyachi
Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Shinji
S
Mii
Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Atsushi
A
Enomoto
Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan.
Yoshiki
Y
Murakumo
Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Takuya
T
Kato
Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Naoya
N
Asai
Division of Vascular Surgery, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Kimihiro
K
Komori
Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: mtakaha@med.nagoya-u.ac.jp.
Masahide
M
Takahashi
D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D017536:Carotid Artery, Common / Q000601:surgery; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D006083:Graft Occlusion, Vascular / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D006965:Hyperplasia; D007601:Jugular Veins / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000637:transplantation*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D058426:Neointima; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism*; D011817:Rabbits; D012039:Regional Blood Flow; D013997:Time Factors; D014162:Transfection
D008840:Microfilament Proteins; D034741:RNA, Small Interfering; C059821:atelocollagen; D003094:Collagen