Effect of Immune Deficiency on Lipoproteins and Atherosclerosis in Male Apolipoprotein E–Deficient Mice

Abstract

Abstract-To determine whether T cells and B cells influence lipid metabolism and atherosclerosis, we crossed apolipoprotein E-deficient (apoE°) mice with recombination activating gene 2-deficient (RAG2°) mice. Total plasma cholesterol levels were Ϸ20% higher in male apoE°mice compared with the apoE°RAG2°mice at 8 weeks of age, and plasma triglyceride levels were 2.5-fold higher in the apoE°mice even when plasma cholesterol levels were similar. Male mice with plasma cholesterol levels between 400 and 600 mg/dL at 8 weeks of age were euthanized at 27 and 40 weeks of age. The aortic root lesion area in the apoE°RAG2°mice, compared with that in the immune-competent apoE°m ice, was 81% and 57% smaller at 27 and 40 weeks of age, respectively. In contrast, there was no difference in the size of the brachiocephalic trunk lesions. Similar results were obtained with mice euthanized at 40 weeks of age that had 8-week cholesterol levels between 300 and 399 mg/dL. In apoE°RAG2°mice, aortic root atherosclerosis was more profoundly suppressed at lower cholesterol levels. Thus, T and B cells and their products differentially influence the development of atherosclerosis at different sites. We also demonstrate a profound effect of the immune system on plasma lipid homeostasis. Key Words: atherosclerosis Ⅲ apolipoprotein E Ⅲ immune deficiency Ⅲ T cells Ⅲ lipoproteins T here is strong circumstantial evidence indicating that the immune response participates in the evolution of atherosclerosis in humans and experimental animals. Many components involved in this response have been detected in atherosclerotic vessels (see review 1 ). T cells are present in human 2 and murine 3 atherosclerotic lesions. Atherosclerotic plaques of apoE-deficient (apoE°) mice contain T cells reactive with oxidized lipoproteins and heat shock proteins. 4 ApoE°mice on a chow diet develop complex lesions throughout the vascular tree, and this occurrence is accelerated by a Western diet. 5,6 These mice have been crossed with recombination activating gene (RAG)1-deficient (RAG1°) and RAG2-deficient (RAG2°) mice. Both of these RAG proteins are necessary for recombination of the T-cell receptor and immunoglobulin genes; thus, RAG°mice lack mature T and B cells. ApoE°RAG1°mice fed a chow diet for 16 weeks showed a 2-fold reduction in aortic root atherosclerosis. 7 The male apoE°RAG1°mice also exhibited modest reductions in plasma cholesterol levels. On the other hand, the extent of atherosclerosis in apoE°mice with either RAG1 or RAG2 deficiency fed a Western diet was similar to that found in immune-competent apoE°mice. 7,8 The role of B cells in the development of atherosclerosis is less clear. Antibodies to oxidized lipoproteins 9 and to heat shock protein 65 10 have been detected in the plasma of subjects with atherosclerotic cardiovascular disease. High titers of circulating autoantibodies to oxidized lipoproteins have also been detected in apoE°mice. 11 Recently, Zhou and Hansson 12 demonstrated the presence of CD22ϩ B cells and IgM in the aortic root lesions...

Lymphocytes Are Not Required for the Rapid Onset of Coronary Heart Disease in Scavenger Receptor Class B Type I/Apolipoprotein E Double Knockout Mice

“…9,31,32 Thus, we compared the plasma lipid levels in dKO and tKO mice because dyslipidemia (hypercholesterolemia, abnormally high unesterified cholesterol [UC] to total cholesterol [TC] ratio) is thought to be responsible for occlusive atherosclerosis and CHD in dKO mice. 2,3 Consistent with previous reports, 9,32 there was a small but significant reduction in plasma UC and phospholipids in tKO animals compared with dKOs (UC [mg/dL] 655Ϯ30 versus 767Ϯ40, respectively, Pϭ0.03; and phospho- lipids [mg/dL] 586Ϯ28 versus 681Ϯ34, respectively, Pϭ0.04) but no statistically significant differences in plasma TCs (909Ϯ38 versus 1001Ϯ54 mg/dL, respectively; Pϭ0. 17) or UC/TC ratios.…”

“…The slightly higher amounts of cholesterol in the very-low-density lipoprotein (VLDL)-size fractions from the dKO mice relative to tKO mice is similar to that reported by Reardon et al for apoE KO mice. 32 The minimal alterations in plasma lipoproteins by RAG2 gene disruption appear unlikely to differentially influence atherosclerosis and CHD in dKO and tKO mice. …”

Using Mice to Dissect Genetic Factors in Atherosclerosis

“…Studies of lesion development at other sites (the distal aorta or the innominate artery, for example) might reveal distinct genetic influences. 41 Curiously, few advanced lesions are observed in the coronary arteries in mouse models. In addition to lesion size, other parameters relevant to atherosclerosis, such as cellular composition, calcification, and lesion-related aneurysms, also vary among inbred strains.…”

Infection withToxoplasma gondiiIncreases Atherosclerotic Lesion in ApoE-Deficient Mice

“…Innate and adaptive immune responses modulate both the rate of lesion progression and composition of atherosclerotic lesions. ApoE knockout (KO) mice crossed into a recombination activating gene (Rag)-deficient background, which lack B and T lymphocytes, had an 80% decrease in the extension of atherosclerotic lesions (32). In addition, crosses of ApoE KO mice with different types of B-or T-cell-deficient mice also decreased atherosclerotic lesions (2,22,40).…”