Inhibition of intimal hyperplasia after vein grafting by in vivo transfer of human senescent cell-derived inhibitor-1 gene.
The senescent cell-derived inhibitor (sdi)-1 (p21) protein has been identified as a downstream mediator of the tumor suppressor p53 in the cell cycle regulation. In this study, we focused on the function of sdi-1 gene in inhibiting vascular smooth muscle cell (VSMC) proliferation after vein grafting in a rabbit model. To test the hypothesis, we transfected human sdi-1 gene by an intra-operative approach. Accompanied by markedly increased sdi-1 protein, the significant increase in PCNA-stained VSMCs in vein grafts was inhibited by transfection of sdi-1 gene. Moreover, at 2 weeks after transfection, transfer of sdi-1 gene resulted in a significant inhibition in neointimal formation, compared with control vector. Of importance, immunohistological studies determining the expression pattern of myosin heavy isoforms, adult type specific SM2 and embryonic specific SMemb/NMHC-B, demonstrated expression of the adult phenotype of VSMCs in the neointima of sdi-1 gene-transfected vein grafts at 2 weeks after the operation, while the neointima was predominantly composed of embryonic phenotype of VSMCs in the control grafts. Overall, these results demonstrate that a single intraluminal incubation of human sdi-1 gene can result in a significant inhibition of neointimal formation after vein grafting, associated with phenotypic change of VSMCs from neonatal to adult type in a rabbit model. Inhibition of hyperplasia in a graft model by transfection of sdi-1 gene may be due to the change in VSMC phenotype from neonatal to adult, in addition to the inhibition of VSMC growth.
Bai
H
H
First Department of Surgery, Osaka University Medical School, Japan.
Morishita
R
R
Kida
I
I
Yamakawa
T
T
Zhang
W
W
Aoki
M
M
Matsushita
H
H
Noda
A
A
Nagai
R
R
Kaneda
Y
Y
Higaki
J
J
Ogihara
T
T
Sawa
Y
Y
Matsuda
H
H
D000199:Actins / Q000032:analysis; D000818:Animals; D001161:Arteriosclerosis / Q000517:prevention & control*; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics*; D004791:Enzyme Inhibitors; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D006965:Hyperplasia; D007150:Immunohistochemistry; D007601:Jugular Veins / Q000637:transplantation*; D011183:Postoperative Complications / Q000517:prevention & control*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011817:Rabbits; D017539:Tunica Intima / Q000473:pathology
D000199:Actins; D015415:Biomarkers; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D018809:Proliferating Cell Nuclear Antigen