on January 6, 2003
Published online before print January 6, 2003, doi: 10.1161/01.CIR.0000051722.66074.60
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Submitted on October 10, 2002
From Institut National de la Santé et de la Recherche Médicale, INSERM U541, and Institut Fédératif de Recherche, IFR Circulation, Université Paris VII, Hôpital Lariboisière, Paris, France (J.B., B.E., A.T., Z.M.); Centre National de la Recherche Scientifique, CNRS, UPR9078 Meudon, and IRNEM Faculté de Médecine Necker, Paris, France (M.C.A.G., S.R., D.R., B.M.); and INSERM U397, Toulouse, France (P.G.). * To whom correspondence should be addressed. E-mail: ziad.mallat{at}larib.inserm.fr.
Background—Uncoupling protein 2 (UCP2) regulates the production of reactive oxygen species in macrophages. However, its role in atherosclerosis is unknown. Methods and Results—Irradiated low-density lipoprotein receptor deficient mice (LDLR-/-) were transplanted with bone marrow from either UCP2 deficient mice (Ucp2-/-) or wild type mice (Ucp2+/+). Mice were fed an atherogenic diet for 7 weeks. Engraftment of bone marrow cells was confirmed by the presence of UCP2 protein expression in spleen cell mitochondria of Ucp2+/+ transplanted mice and its absence in Ucp2-/- transplanted mice. Leukocyte counts and plasma cholesterol levels were comparable in both groups. We found a marked increase in atherosclerotic lesion size in the thoracic aorta of Ucp2-/- transplanted mice compared with control Ucp2+/+ transplanted mice (8.3±0.9% versus 4.3±0.4%, respectively; P<0.005), as well as in the aortic sinus (150 066±12 388 µm2 versus 105 689±9 727 µm2, respectively; P<0.05). This was associated with increased nitrotyrosine staining, which suggests enhanced oxidative stress. Analysis of plaque composition revealed a significant increase in macrophage accumulation (P<0.05) and apoptosis (P<0.05), along with a decrease in collagen content (P<0.05), suggesting a potentially more vulnerable phenotype. Conclusion—These results suggest a protective role for UCP2 against atherosclerosis.
Revised on November 20, 2002
Accepted on November 21, 2002
Protective Role of Uncoupling Protein 2 in Atherosclerosis
J. Blanc MD,
Key words: atherosclerosis • free radicals • inflammation
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