Regulation of vein graft hyperplasia by survivin, an inhibitor of apoptosis protein.
OBJECTIVE
Survivin (SVV) is an inhibitor of apoptosis protein (IAP) that is upregulated in cancer and has recently been implicated in vascular injury. We sought to investigate the role of SVV in vein graft hyperplasia.


RESULTS
Adenoviral constructs expressing a dominant-negative (AdT34A) and wild-type (AdWT) SVV were used. Proliferation and apoptosis were assayed on endothelial cells (ECs) and smooth muscle cells (SMCs) from human saphenous vein. A rabbit carotid interposition vein graft model (N=31) was used, with adventitial gene transfer of SVV constructs. In vitro, overexpression of SVV was associated with protection from cytokine-induced apoptosis in ECs and SMCs; conversely, AdT34A directly induced apoptosis in these cells. SMC proliferation was increased by AdWT infection, whereas AdT34A reduced proliferation; both effects were serum-dependent. Expression of platelet-derived growth factor (PDGF) in SMCs was regulated by functional SVV expression in analogous fashion. In vivo, proliferation and apoptosis (7 days), as well as wall thickness (30 days), were modified by adenoviral-mediated SVV expression. Adventitial angiogenesis was regulated by the SVV-expressing constructs in a fashion parallel to wall thickness changes.


CONCLUSIONS
SVV is a critical regulator of multiple processes, including proliferation, apoptosis, and angiogenesis, that determine the remodeling response of vein grafts following arterialization.
Wang
Grace J
GJ
Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Sui
Xin Xin
XX
Simosa
Hector F
HF
Jain
Mukesh K
MK
Altieri
Dario C
DC
Conte
Michael S
MS
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002339:Carotid Arteries / Q000473:pathology / Q000601:surgery*; D002340:Carotid Artery Diseases / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005822:Genetic Vectors; D006085:Graft Survival / Q000502:physiology*; D006801:Humans; D006965:Hyperplasia; D051034:Inhibitor of Apoptosis Proteins; D007601:Jugular Veins / Q000473:pathology / Q000637:transplantation*; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011817:Rabbits; D012501:Saphenous Vein / Q000166:cytology; D015398:Signal Transduction / Q000502:physiology; D000077022:Survivin
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D010982:Platelet-Derived Growth Factor; D000077022:Survivin