on December 29, 2003
Published online before print December 29, 2003, doi: 10.1161/01.ATV.0000114235.51044.92
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Submitted on August 19, 2003
Accepted on December 11, 2003
Adenoviral Transfer of Endothelial Nitric Oxide Synthase Attenuates Lesion Formation in a Novel Murine Model of Postangioplasty Restenosis
Jan H. von der Thüsen *;
From the Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research (J.H.v.d.T., T.J.C.v.B., E.A.L.B.), Gorlaeus Laboratories, Department of Cardiology, Leiden University Medical Centre (J.H.v.d.T., M.L.F.), and Crucell Holland B.V. (R.P., A.J.v.Z., V.M.), 2333 CN Leiden, The Netherlands.
* To whom correspondence should be addressed. E-mail: thuesen{at}lacdr.leidenuniv.nl.
Objective--Restenosis remains a major late complication of percutaneous transluminal coronary angioplasty (PTCA), for which the development of prevention strategies has thus far been hampered by the lack of a representative and practical animal model. We have, therefore, developed a murine model of PTCA-induced restenosis.
Methods and Results--Rigid probe angioplasty of pre-existing atherosclerotic lesions in the carotid arteries of ApoE-deficient mice was found to result in an increase in lesion size (0.14±0.04x105 µm2 to 0.42±0.09x105 µm2, P=0.007) with a smooth muscle cell-rich, fibrotic lesion morphology. In an additional experiment, lesions were incubated immediately after angioplasty with adenovirus bearing an endothelial nitric oxide synthase (eNOS) transgene (Ad.APT.eNOS), or an "empty" control virus (Ad.APT.empty) at a titer of 1.5x109 pfu/mL. Ad.APT.eNOS treatment was seen to lead to a 73.1% reduction in plaque size (0.27±0.04x105 µm2 versus 1.02±0.39x105 µm2, P=0.07), which translated to a significantly lowered average degree of stenosis (33.6±4.1% versus 74.6±14.0%, P=0.02). Ad.APT.eNOS also decreased lesional collagen content from 29.1% to 4.8% (P<0.001).
Conclusion--We believe that we have established a representative murine model of postangioplasty restenosis, which may serve to elucidate the mechanisms underlying restenosis and to evaluate potential antirestenotic therapies.
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