Aggressive Very Low-Density Lipoprotein (VLDL) and LDL Lowering by Gene Transfer of the VLDL Receptor Combined with a Low-Fat Diet Regimen Induces Regression and Reduces Macrophage Content in Advanced Atherosclerotic Lesions in LDL Receptor-Deficient Mice
| Autor: | Stephen M. Schwartz, Bardia Askari, Rebecca M. Varon, Lawrence Chan, Shelley Barnhart, Kazuhiro Oka, Erin D. MacDougall, Farah Kramer, Fredrik Johansson, Karin E. Bornfeldt, Patti Polinsky, Michael E. Rosenfeld |
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| Rok vydání: | 2006 |
| Předmět: |
medicine.medical_specialty
Very low-density lipoprotein Genetic Vectors VLDL receptor Mice Transgenic Lipoproteins VLDL Biology Pathology and Forensic Medicine Lesion Mice Internal medicine medicine Animals Receptor Diet Fat-Restricted Vascular disease Macrophages Genetic transfer Gene Transfer Techniques Atherosclerosis medicine.disease Lipoproteins LDL Mice Inbred C57BL Cholesterol Glucose Endocrinology Receptors LDL LDL receptor lipids (amino acids peptides and proteins) medicine.symptom Regular Articles Lipoprotein |
| Zdroj: | The American Journal of Pathology. 168:2064-2073 |
| ISSN: | 0002-9440 |
| DOI: | 10.2353/ajpath.2006.051009 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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