RESUMO
OBJECTIVE: Osteoprotegerin (OPG), a member of the tumor necrosis factor (TNF) superfamily of proteins, plays an important role in bone remodeling and is expressed in both mouse and human atherosclerotic lesions. The current study was designed to assess whether OPG plays a role in the progression and calcification of advanced atherosclerotic lesions in apoE(-/-) mice. METHODS AND RESULTS: Atherosclerotic lesion area and composition and aortic calcium content were examined in mice deficient in both OPG and apolipoprotein E (OPG(-/-).apoE(-/-) mice) at 20, 40, and 60 weeks of age. Littermate OPG(+/+).apoE(-/-) mice were used as controls. The average cross-sectional area of lesions in the innominate arteries was increased in OPG(-/-).apoE(-/-) mice at 40 and 60 weeks of age. The increase in lesion area was coupled with a reduced cellularity and an increase in connective tissue including laminated layers of elastin. Sixty-week-old OPG(-/-).apoE(-/-) mice also had an increase in the area of calcification of the lesions. There were no differences in markers of plaque stability. In vitro, OPG induced matrix metalloproteinase-9 (MMP-9) activity in macrophages and smooth muscle cells and acted as a survival factor for serum-deprived smooth muscle cells. CONCLUSIONS: OPG inhibits advanced plaque progression by preventing an increase in lesion size and lesion calcification. OPG may act as a survival factor and may modulate MMP9 production in vascular cells.
Assuntos
Envelhecimento , Aterosclerose/metabolismo , Aterosclerose/patologia , Calcinose/metabolismo , Calcinose/patologia , Glicoproteínas/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Animais , Aorta/metabolismo , Aorta/patologia , Aorta/fisiopatologia , Tronco Braquiocefálico/metabolismo , Tronco Braquiocefálico/patologia , Calcinose/prevenção & controle , Cálcio/metabolismo , Proteínas de Transporte/metabolismo , Sobrevivência Celular , Progressão da Doença , Feminino , Glicoproteínas/sangue , Glicoproteínas/genética , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout/genética , Miócitos de Músculo Liso/metabolismo , Osteoprotegerina , Ligante RANK , Receptor Ativador de Fator Nuclear kappa-B , Receptores Citoplasmáticos e Nucleares/sangue , Receptores Citoplasmáticos e Nucleares/genética , Receptores do Fator de Necrose Tumoral/sangue , Receptores do Fator de Necrose Tumoral/genéticaRESUMO
Very low-density lipoprotein (VLDL) and LDL plasma levels are associated with cardiovascular mortality. Whereas VLDL/LDL lowering causes regression of early atherosclerotic lesions, less is known about the effects of aggressive lipid lowering on regression of advanced complex lesions. We therefore investigated the effect of VLDL/LDL lowering on pre-existing lesions in LDL receptor-deficient mice. Mice fed a high-fat diet for 16 weeks developed advanced lesions with fibrous caps, necrotic cores, and cholesterol clefts in the brachiocephalic artery. After an additional 14 weeks on a low-fat diet, plasma cholesterol levels decreased from 21.0 +/- 2.6 to 8.4 +/- 0.6 mmol/L, but lesions did not regress. Levels of VLDL/LDL were further lowered by using a helper-dependent adenovirus encoding the VLDL receptor (HD-Ad-VLDLR) under control of a liver-selective promoter. Treatment with HD-Ad-VLDLR together with a low-fat diet regimen resulted in reduced lesion size (cross-sectional area decreased from 146,272 +/- 19,359 to 91,557 +/- 15,738 microm2) and an 89% reduction in the cross-sectional lesion area occupied by macrophages compared to controls. These results show that aggressive VLDL/LDL lowering achieved by hepatic overexpression of VLDLR combined with a low-fat diet regimen induces regression of advanced plaques in the brachiocephalic artery of LDL receptor-deficient mice.