Tissue-selective expression of dominant-negative proteins for the regulation of vascular smooth muscle cell proliferation.
The transcription factors c-myb and c-myc are essential for vascular smooth muscle cell (VSMC) replication and are rapidly induced following mitogenic stimulation of quiescent VSMCs in vitro and in vivo following balloon catheter injury. Consequently, interference with c-myb and c-myc function provides a possible avenue for the prevention of VSMC proliferation associated with intimal hyperplasia. We have carried out studies focused on the inhibition of VSMC proliferation using dominant-negative gene constructs incorporating the DNA-binding domains of the c-myb or c-myc genes fused to the repressor domain of the Drosophila engrailed gene. Transient transfection of rat, rabbit and human vascular SMCs results in a dramatic inhibition of proliferation for at least 72 h after transfection. Furthermore, this inhibition of cellular proliferation was found to be due, at least in part, to the induction of apoptosis. Coupling expression of the chimeric dominant-negative proteins to transcriptional regulatory elements of the human vascular smooth muscle alpha-actin gene allows specific targeting of vascular smooth muscle cells.
Schmitt
J F
JF
Thrombosis Research Institute, London, UK.
Keogh
M C
MC
Dennehy
U
U
Chen
D
D
Lupu
F
F
Weston
K
K
Taylor
D
D
Kakkar
V V
VV
Lemoine
N R
NR
D000199:Actins / Q000378:metabolism; D002455:Cell Division; D016259:Genes, myc / Q000235:genetics*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D014162:Transfection / Q000379:methods
D000199:Actins; D020598:Proto-Oncogene Proteins c-myb; D011993:Recombinant Fusion Proteins