doi: 10.1161/hq1101.098552
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© 2001 American Heart Association, Inc.
Vascular Biology |
Localization of c-Myb and Induction of Apoptosis by Antisense Oligonucleotide c-myb After Angioplasty of Porcine Coronary Arteries
From the Cardiovascular Research Group (D.L.L., L.S., J.G., S.E.F., A.K., D.C. Crossman, D.C. Cumberland), Division of Clinical Sciences, University of Sheffield, Sheffield, UK, and the Unit of Cardiac Physiology (N.M., C.M.H.), Stopford Building, University of Manchester, Manchester, UK.
Reprint requests to Dr C.M. Holt, Unit of Cardiac Physiology, University of Manchester, 1.305 Stopford Building, Oxford Road, Manchester M13 9PT, UK. E-mail cathy.holt{at}man.ac.uk
Abstract—— Previous studies have shown that inhibition of the proto-oncogene c-myb inhibits neointimal formation in various animal models. However, the temporal and spatial expression of c-Myb in the vessel wall after injury is not known, and the mechanism of action of antisense oligonucleotide (AS-ODN-c-myb) inhibition remains unclear. One potential effect of cell cycle dysregulation by inhibition of c-myb is an increase in the rates of apoptosis. In this study, c-Myb expression after percutaneous transluminal coronary angioplasty (PTCA) injury and induction of apoptosis after AS-ODN-c-myb treatment were determined. Immunohistochemistry and cellular phenotyping were used to localize c-Myb expression in porcine coronary arteries at various time intervals after PTCA. In vitro, the effects of AS-ODN-c-myb on the apoptosis of porcine vascular smooth muscle cells (PVSMCs) and endothelial cells were determined by using a cell-death ELISA and time-lapse video microscopy. In vivo, local delivery of AS-ODN-c-myb was performed after PTCA of pig coronary arteries, and apoptosis was quantified at 6 hours. c-Myb is induced in pig coronary arteries after angioplasty, with maximal expression in inflammatory cells at 18 hours and in vascular smooth muscle cells at 3 to 7 days. In vitro, AS-ODN-c-myb enhanced PVSMCs (6.8±0.8% [P=<0.001] versus 0.5% serum) but not endothelial cell apoptosis (1.4±0.5% [P=NS] versus 0.5% serum). In vivo, 6 hours after porcine coronary angioplasty and delivery of AS-ODN-c-myb, the proportion of apoptotic cells within the media was 4.2±0.8% (PTCA alone), 2.3±0.2% (PTCA+vehicle), and 9.0±1.1% (PTCA+AS-ODN-c-myb; P<0.05 versus PTCA alone and P<0.01 versus PTCA+saline). c-Myb is expressed after PTCA of pig coronary arteries, and AS-ODN-c-myb induces apoptosis of PVSMCs in vitro and medial cells in vivo.
Key Words: angioplasty • proto-oncogenes • antisense • apoptosis
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