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

Abstract

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 highfat 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. Dyslipidemia is a central risk factor for cardiovascular disease and is the primary target for prevention of cardiovascular mortality.1 Modification of low-density lipoproteins (LDL) is considered a key contributor to cardiovascular disease in the general population.2 Furthermore, levels of VLDL/triglycerides are often elevated in patients with type 2 diabetes or the metabolic syndrome, 3 and increased level of triglycerides is considered a risk factor for atherosclerotic heart disease in patients with and without diabetes. 4,5 The great majority of acute clinical cardiovascular events, myocardial infarction and stroke, are believed to be caused by unstable atherosclerotic lesions.6,7 Studies of human atherosclerotic lesions have indicated that most clinically relevant lesions are composed of necrotic cores covered by thin fibrous caps containing macrophage-rich re-

An Inducible and Reversible Mouse Genetic Rescue System

“…Doxtreatment of ApoE iKO mice results in expression of ApoE, marked reduction of plasma cholesterol levels, and regression of aortic atherosclerotic lesions. These findings are consistent with previous studies showing that aggressive lipid lowering or expression of ApoE can induce regression of pre-existing atherosclerotic lesion [7,8,34,35]. It is becoming increasingly clear that lesion regression is regulated by a complex interplay between lipids, inflammation and the immune system [35].…”

Do Glucose and Lipids Exert Independent Effects on Atherosclerotic Lesion Initiation or Progression to Advanced Plaques?

“…[55][56] Diabetes has been associated with increased expression of receptors associated with uptake of modified LDL, such as CD36, scavenger receptor A, and lectin-like oxidized LDL receptor (LOX-1); and reduced levels of the reverse cholesterol transporters ATP-binding cassette A1 (ABCA1) and ABCG1, all of which could accelerate accumulation of intracellular cholesterol and potentially necrotic core formation. [57][58][59][60][61] However, further studies are needed to investigate whether the ability of macro- 17 Lamharzi et al, 38 and MacDougall et al 76 *Processes stimulated by diabetes.…”

Type 1 diabetes promotes disruption of advanced atherosclerotic lesions in LDL receptor-deficient mice

“…Bone marrow was harvested from femurs of C57BL/6 mice and allowed to differentiate into macrophages in the presence of 15% L-conditioned medium, as a source of macrophage colony-stimulating factor (M-CSF). Other methods have been described (13,31), or are described in SI Text.…”