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Lipoprotein classes and susceptibility to atherosclerosis

Institution: J. David Gladstone Institutes
Investigator(s): Stephen Young, M.D.
Award Cycle: 1998 (Cycle 7) Grant #: 7RT-0032 Award: $702,940
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Cigarette smoking causes life threatening pulmonary diseases such as emphysema and lung cancer. Smoking is also a potent risk factor for atherosclerotic coronary heart disease, as well as occlusive peripheral vascular disease. Many potential mechanisms for the pro atherogenic effects of cigarette smoke have been suggested. However, most investigators agree that at least a portion of smoking's pro atherogenic effects are mediated through changes in plasma lipoproteins (i.e., blood proteins that transport fats). Smokers have higher levels of very low density lipoproteins (VLDL) and plasma triglycerides than nonsmokers, but they have lower levels of high density lipoproteins (HDL)-bound cholesterol (i.e., the “good” form of cholesterol) than nonsmokers. In addition, cigarette smoking probably promotes the oxidation of apolipoprotein B100 containing low density lipoproteins (LDL). Oxidized LDL are thought to promote the formation of early, lipid rich atherogenic plaques through a number of different mechanisms.

Despite these clues into smoking's effects on plasma lipoproteins, many fundamental questions remain regarding the relationship between the plasma lipoproteins and atherogenesis. For smokers and nonsmokers alike, it is simply not clear which lipoproteins in particular are the most atherogenic. Cholesterol rich LDL (i.e., the “bad” form of cholesterol) might be the main culprit in atherosclerosis, but also VLDL intermediate density lipoproteins (IDL) might be particularly atherogenic. The principal objective of this project is to determine if VLDL and LDL differ in their abilities to promote atherosclerosis. To address this issue, we propose to analyze susceptibility to atherosclerosis in chow fed, serum cholesterol matched mice in which the cholesterol is carried exclusively in the VLDL fraction, or exclusively in the LDL fraction. In Specific Aim 1, we will characterize the plasma lipoproteins and apolipoproteins in the VLDL cholesterol and LDL cholesterol mice. We will test the hypothesis that the chow fed VLDL cholesterol and LDL cholesterol mice have different susceptibilities to atherosclerosis, despite having identical total plasma cholesterol levels. We will also test whether the number and location of lesions within major arteries (e.g., the aorta) differs in the two groups of mice. In Specific Aim 2, we will use metabolic studies to determine if there are differences in the retention of VLDL and LDL within the arterial wall, and whether these differences correlate with the location of atherosclerotic lesions and the extent of their development.

Final Report
Despite clues regarding smoking’s effects on the plasma lipoproteins, many fundamental questions about the relationship between the plasma lipoproteins and atherogenesis remain unanswered. It has not been clear, for example, which classes of lipoproteins are the most atherogenic. Small, cholesterol ester–rich LDL might be the main culprit in atherosclerosis, but some investigators believe that larger VLDL and chylomicron remnant particles might be particularly atherogenic. The principal objective of our project has been to determine if VLDL and LDL differ in their intrinsic ability to promote atherosclerosis. To address this issue, we designed a study to compare the extent of atherosclerosis in two groups of chow-fed mice that have nearly identical plasma cholesterol levels: LDL receptor–deficient apo-B100-only mice (Ldlr–/–Apob100/100) (in which nearly all of the cholesterol in the plasma is on small, LDL particles) and apo-E-deficient apo-B100-only mice (Apoe–/–Apob100/100) (where nearly all of the cholesterol is carried on VLDL particles. Morphometric analyses of aortic atherosclerotic lesions yielded definitive results. The Ldlr–/–Apob100/100 mice had nearly 300% more atherosclerosis than the Apoe–/–Apob100/100 mice, even though their total plasma cholesterol levels were identical. This study was published in The Journal of Clinical Investigation. Recently, we summarized our studies in an invited review for Arteriosclerosis, Thrombosis, and Vascular Biology.

During the past year, we have worked an animal model for assessing the regression of atherosclerosis and gene expression changes that accompany regression. We hypothesized that both the hypercholesterolemia and the susceptibility to atherosclerosis could be eliminated by switching off hepatic lipoprotein production. To test this hypothesis, we bred “AtheroReversa mice”—Apoe–/–Apob100/100 mice that were homozygous for a conditional allele of microsomal triglyceride transfer protein (Mttp) and homozygous for the Mx1-Cre transgene. Expression of Cre from the Mx1-Cre transgene can be induced with injections of polyinosinic-polycytidylic ribonucleic acid (pIpC). Treatment of AtheroReversa mice with pIpC virtually eliminated Mttp expression in the liver (as judged by quantitative RT-PCR assays), abolished lipoprotein secretion by the liver (as judged by transmission electron microscopy), and eliminated LDL cholesterol from the plasma (as judged by FPLC fractionation experiments). Both plasma triglyceride levels and cholesterol levels fell dramatically in pIpC-treated mice, both on chow and high-fat diets. AtheroReversa mice should be ideal for studying regression of atherosclerosis and investigating changes in arterial gene expression that accompany hypercholesterolemia and atherogenesis.
Publications

Defining the atherogenicity of large and small lipoproteins containing apolipoprotein B100
Periodical: Journal of Clinical Investigation Index Medicus:
Authors: Veniant MM, Sullivan Ma, Kim SK, et al ART
Yr: 2000 Vol: 106 Nbr: Abs: Pg: 1501-1510

Atheroslerosis susceptibility in Chow-fed apoe-1- and Ldlr-1- mice matched for total plasma cholesterol levels
Periodical: Arteriosclerosis, Thrombosis, and Vascular Biology Index Medicus:
Authors: Veniant MM, Withycombe S, Young SG ART
Yr: 0 Vol: Nbr: Abs: Pg:

Lipoprotein size and atherosclerosis susceptibility in Apoe-/- and Ldlr-/- mice.
Periodical: Arteriosclerosis, Thrombosis, and Vascular Biology Index Medicus:
Authors: Veniant MM, Withycombe S, and Young SG ART
Yr: 2001 Vol: 21 Nbr: Abs: Pg: 1567 - 1570