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© 1997 American Heart Association, Inc.
Articles |
The Effect of Oligonucleotides to c-myb on Vascular Smooth Muscle Cell Proliferation and Neointima Formation After Porcine Coronary Angioplasty
From the Sections of Cardiology (J.G., S.E.F., C.M.H.N., D.C. Crossman), Interventional Cardiology (J.G., D.C. Cumberland), and Cardiothoracic Surgery (C.M.H., L.S., M.G.), University of Sheffield, Clinical Sciences Centre, Northern General Hospital, Sheffield, UK.
Correspondence to Julian Gunn, Section of Cardiology, Clinical Sciences Centre, Northern General Hospital, Herries Road, Sheffield S5 7AU, UK. E-mail J.Gunn{at}Sheffield.ac.uk
Abstract Proto-oncogenes, including c-myb, are expressed early after vascular injury. The application of antisense oligodeoxynucleotides (AS-ODNs) against these genes inhibits cell proliferation and neointima formation in small animals and in peripheral arteries. The aim of this study was to investigate the specificity of action of AS-ODN–c-myb in vitro and to assess its effect, when delivered locally, on neointima formation after percutaneous transluminal coronary angioplasty (PTCA) in porcine coronary arteries. AS-ODN–c-myb inhibited the proliferation of vascular smooth muscle cells (VSMCs) in vitro in a dose-dependent manner. There was a corresponding reduction in steady state levels of c-myb mRNA and protein. Expression of another early gene, c-fos, was unaffected. S1 nuclease analysis demonstrated intact full-length AS-ODN–c-myb retrieved from VSMCs in culture after 12 hours. A range of ODNs, related and unrelated to c-myb, with and without a GGGG sequence, inhibited VSMC proliferation. Phosphorothioated AS-ODN–c-myb was 30 times less potent than unphosphorothioated AS-ODN–c-myb. PTCA induced porcine coronary artery neointima formation. c-myb mRNA was maximally induced 18 hours after injury. Unmodified AS-ODN–c-myb, sense-ODN–c-myb, saline, or nothing was delivered immediately after balloon dilatation via a double-skinned porous balloon (Transport, SciMed). Fluorescence-labeled AS-ODN–c-myb was deposited throughout the vessel wall. Mean maximum intima/media cross-sectional area 4 weeks after PTCA was reduced with AS-ODN–c-myb by 79% compared with saline (P<.05), 82% compared with sense-ODN–c-myb, and 63% compared with nothing (P<.10). Conclusions are as follows: (1) c-myb is expressed in VSMCs after vascular injury. (2) AS-ODN–c-myb is retained intact in VSMCs, reducing their proliferation in vitro in dose-dependent fashion, with reduction in c-myb mRNA and protein, whereas sense-ODN–c-myb is not. (3) A range of ODNs can reduce VSMC proliferation by a non–sequence-specific mechanism. (4) Phosphorothioate protection of antisense molecules may reduce their efficacy. (5) Local delivery of unmodified AS-ODN–c-myb via the Transport catheter reduces neointima formation after porcine PTCA. (6) Local delivery of fluid may exacerbate neointimal thickening.
Key Words: c-myb • smooth muscle cell proliferation • antisense oligomer • local delivery • restenosis
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