Angiotensin II and tumor necrosis factor-alpha upregulate survivin and Kruppel-like factor 5 in smooth muscle cells: Potential relevance to vein graft hyperplasia.
BACKGROUND
Survivin (SVV) is a unique inhibitor of apoptosis protein (IAP) that regulates both apoptosis and mitosis. Recent work suggests that SVV plays a critical role in the vascular injury response, but the molecular pathways remain unclear.


METHODS
We examined the expression of SVV and the transcription factor, KLF5, in human venous smooth muscle cells (VSMC) by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot analysis after treatment with angiotensin II (Ang II) or tumor necrosis factor-alpha (TNF-alpha). An adenoviral construct expressing SVV or GFP was also employed to assess effects on KLF5 expression. A rabbit carotid interposition vein graft model was used to assess the relevance of KLF5 to bypass graft healing.


RESULTS
Stimulation of VSMC with Ang II and TNF-alpha led to a rapid upregulation of KLF5 expression, and a later increase in SVV, which was cell-cycle independent. Overexpression of SVV in VSMC led to an early and persistent induction of KLF5. KLF5 was upregulated in rabbit vein grafts early (1 day) after grafting.


CONCLUSIONS
We speculate that SVV is a central point of convergence of multiple signaling pathways in vascular injury, and that it regulates the local amplification of these pathways in the vessel wall.
Bafford
Richard
R
Vascular Surgery Research Laboratory, Brigham and Women's Hospital, Boston, MA 02115, USA.
Sui
Xin Xin
XX
Wang
Grace
G
Conte
Michael
M
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D002339:Carotid Arteries / Q000601:surgery; D018929:Cell Culture Techniques; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins; D007601:Jugular Veins / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D012501:Saphenous Vein / Q000166:cytology / Q000378:metabolism; D000077022:Survivin; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D000077022:Survivin; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II