Abstract-The role of insulin resistance (IR) in atherogenesis is poorly understood, in part because of a lack of appropriate animal models. We assumed that fructose-fed LDL receptor-deficient (LDLR Ϫ/Ϫ ) mice might be a model of IR and atherosclerosis because (1) fructose feeding induces hyperinsulinemia and IR in rats; (2) a preliminary experiment showed that fructose feeding markedly increases plasma cholesterol levels in LDLR Ϫ/Ϫ mice; and (3) hypercholesterolemic LDLR Ϫ/Ϫ mice develop extensive atherosclerosis. To test whether IR could be induced in LDLR Ϫ/Ϫ mice, 3 groups of male mice were fed a fructose-rich diet (60% of total calories; nϭ16), a fat-enriched (Western) diet intended to yield the same plasma cholesterol levels (nϭ18), or regular chow (nϭ7) for approximately 5.5 months. The average cholesterol levels of both hypercholesterolemic groups were similar (849Ϯ268 versus 964Ϯ234 mg/dL) and much higher than in the chow-fed group (249Ϯ21 mg/dL). Final body weights in the Western diet group were higher (39Ϯ6.2 g) than in the fructose-(27.8Ϯ2.7 g) or chow-fed (26.7Ϯ3.8 g) groups. Contrary to expectation, IR was induced in mice fed the Western diet, but not in fructose-fed mice. The Western diet group had higher average glucose levels (187Ϯ16 versus 159Ϯ12 mg/dL) and 4.5-fold higher plasma insulin levels. Surprisingly, the non-insulin-resistant, fructose-fed mice had significantly more atherosclerosis than the insulin-resistant mice fed Western diet (11.8Ϯ2.9% versus 7.8Ϯ2.5% of aortic surface; PϽ0.01). These results suggest that (1) Key Words: arteriosclerosis Ⅲ diabetes Ⅲ fructose Ⅲ hypercholesterolemia Ⅲ lipoproteins I ndividuals with underlying insulin resistance (IR) and resulting impaired glucose tolerance (IGT) and noninsulin-dependent diabetes mellitus (NIDDM) have an increased prevalence of atherosclerosis and increased rates of coronary heart disease (CHD), 1-5 but the mechanisms responsible are poorly understood. Hyperglycemia has been hypothesized to enhance atherosclerosis in NIDDM, but the specific contribution of hyperglycemia has been difficult to demonstrate in either population studies or animal models. [5][6][7][8] Moreover, hyperglycemia per se is unlikely to play a role in the development of atherosclerosis in individuals with IGT who usually demonstrate only modest postprandial hyperglycemia. Insulin resistance is frequently associated with a number of metabolic abnormalities such as obesity, hypertriglyceridemia, low HDL, and hypertension. These risk factors explain some, but not all, of the increased risk for CHD. 9,10 Thus, additional factors associated with IR are likely to contribute to the accelerated development of atherosclerosis. Hyperinsulinemia is frequently present in both IGT and NIDDM, and several lines of evidence suggest that hyperinsulinemia itself may be proatherogenic. 11,12 For example, insulin has been shown to increase smooth muscle cell proliferation in vitro 11,13 and to enhance accumulation of cholesterol ester in aortas of rats. 14 Although several mechani...
Investigations into the mechanisms by which diabetes accelerates atherosclerosis have been hampered by the lack of suitable animal models. We hypothesized that streptozotocin-treated LDL receptor-deficient mice would be a good model of diabetic atherosclerosis because streptozotocin causes diabetes in the parent C57BL/6 strain and because in these mice diet-induced hypercholesterolemia leads to the formation of advanced atherosclerotic lesions throughout the aorta. Diabetes was induced in 18 mice by intraperitoneal injection of streptozotocin. Low-dose insulin was given subcutaneously to prevent excessive mortality and extreme elevations in triglyceride levels. The control group was subjected to sham injections. Both groups were fed a diet containing .075% cholesterol for six months. Average blood glucose was higher in the diabetic group than in the control group (257 +/- 67 mg/dL versus 111 +/- 7 mg/dL, P < 0.05). Although plasma cholesterol was similar (966 +/- 399 versus 1002 +/- 180 mg/dL) in both groups, VLDL cholesterol was higher whereas LDL cholesterol was lower in the diabetic group. Immunocytochemical analysis demonstrated significantly more advanced glycation end-product (AGE) epitopes in the artery wall of the diabetic group, whereas staining for oxidation-specific epitopes was similar in both groups. Sera of diabetic mice also contained significantly more IgG autoantibodies that bound to several AGE epitopes than did sera from control mice. Despite the presence of hyperglycemia, diabetic dyslipidemia, and enhanced AGE formation in the diabetic mice, both groups had a similar extent of atherosclerosis (diabetic, 17.3 +/- 5.2; control, 16.5 +/- 6.6% of the aortic surface). These data suggest that, at least under conditions of marked hypercholesterolemia; hyperglycemia and enhanced AGE formation do not contribute significantly to atherogenesis in LDL-/- mice.
Abstract-Transgenic and knockout mice are widely used as models for atherogenesis studies. While developing aHelicobacter infection model in LDL receptor-negative (LDLR Ϫ/Ϫ ) mice, we noticed that mice fed a high-fat, high-cholesterol diet often contracted gastritis independent of infection. To further investigate this finding, we studied 27 male and 18 female LDLR Ϫ/Ϫ mice fed high-fat, 1% or 1.25% cholesterol diets for 3 to 4 months. The extent of atherosclerosis was morphometrically analyzed in the whole aorta, and the degree of gastric inflammation was scored histologically in hematoxylin-eosin-stained stomach sections. The autoantibody titers to epitopes of oxidized LDL were also measured. Mice fed high-fat, high-cholesterol diets had a significantly higher incidence of gastritis than mice fed normal chow, 62% versus 5%, respectively (PϽ0.0001). This effect was specific for LDLR Ϫ/Ϫ mice, because no difference in gastritis was found in wild-type mice fed either diet. Animals with gastritis showed slightly more atherosclerosis than animals without gastritis: 16.3Ϯ6.4% versus 12.8Ϯ3.4% in males and 9.4Ϯ3.5% versus 6.5Ϯ3.3% in females. Cholesterol-fed mice also had significantly higher IgG autoantibody titers against modified LDL than normal chow-fed animals, but no difference was seen between the gastritis and nongastritis groups. We conclude that the standard high-fat, high-cholesterol diet commonly used in many murine models to induce atherosclerosis increased the incidence of gastritis significantly in LDLR Key Words: inflammation Ⅲ atherosclerosis Ⅲ gastritis M ice are rapidly becoming a preferred model for studies of atherosclerosis. Most wild-type mice are generally resistant to hypercholesterolemia and atherogenesis, even when placed on a high-fat, high-cholesterol diet. C57BL/6 mice, however, have an increased susceptibility to atherosclerosis, 1 and a large number of transgenic and gene-knockout models based on this genetic background develop substantial hypercholesterolemia and atherosclerosis. 2 In these models, the development of transitional and advanced atherosclerotic lesions in the aortic origin and throughout the aorta is generally dependent on prolonged feeding of high-fat, highcholesterol diets. For example, LDL receptor-negative (LDLR Ϫ/Ϫ ) mice fed normal murine chow develop plasma cholesterol levels of Ϸ250 mg/dL and limited atherosclerosis, whereas high-cholesterol diets induce cholesterol levels Ͼ1200 mg/dL and extensive atherosclerosis throughout the aortic tree. 3,4 In contrast, apolipoprotein (apo) E-deficient (apoE Ϫ/Ϫ ) mice spontaneously develop substantial hypercholesterolemia and atherosclerosis even on a normal chow diet. 5,6 Nevertheless, many studies in apoE Ϫ/Ϫ mice use "Western" diets with increased cholesterol content to further raise plasma cholesterol levels and accelerate lesion formation. 3,[7][8][9] Mice fed high-cholesterol diets have been used extensively to study atherogenic mechanisms of apoproteins and lipoproteins, lipoprotein and scavenger receptors, the role ...
Although age is a strong risk factor for atherosclerosis, it is unclear whether age may directly influence the process of atherogenesis. We, therefore, performed several studies in young (2-4 months old), mature (10-14 months old), and old (20-22 months old) mice to determine if the rate of aortic lesion formation increases with age, and whether this is related to increases in oxidative stress or vascular cell adhesion molecule (VCAM-1) expression in the aortic wall. In chow-fed low-density lipoprotein receptor-deficient (LDLR-/-) mice, plasma total cholesterol levels increased with age (250 +/- 52 mg/dl in young, 276 +/- 58 in mature, and 314 +/- 101 mg/dl in old mice). In contrast, the extent of atherosclerosis rose more rapidly, increasing from 3.6 +/- 2.7% of the aortic surface in mature mice to 18.2 +/- 8% in old mice. Plasma and tissue levels of antioxidant enzymes and molecules, as well as plasma thiobarbituric acid reactive substances and low-density lipoprotein susceptibility to oxidation, did not change with age. In a second study, VCAM-1 expression in the aortic arch and the extent of atherosclerosis in the aortic origin were significantly greater in old LDLR-/- mice than in young LDLR-/- mice. Additionally, after 1 month of a high-fat diet, which induced equally elevated plasma cholesterol levels in both young and old LDLR-/- mice, VCAM-1 expression and aortic lesion formation were still greater in old mice. The extent of atherosclerosis correlated well (r = .65,p <.01) with the expression of VCAM-1 in the aortic origin. In a final study, we measured VCAM-1 expression and atherosclerosis in young, mature, and old C57BL/6 mice, which have low plasma cholesterol levels (< or =100 mg/dl) when fed a standard chow diet. Although plasma cholesterol levels did not increase with age, old C57BL/6 mice had significantly more VCAM-1 expression in the aortic arch than did young mice. However, no lesions were observed in the aortic origin in either group. These data demonstrate that plasma cholesterol levels and VCAM-1 expression increase with age and suggest that this may contribute to the increased rate of atherosclerotic lesion formation in LDLR-/- mice. Importantly, the age-dependent increase in VCAM-1 expression does not appear to be related to plasma cholesterol levels. This study also suggests that in the absence of elevated plasma cholesterol, an increased expression of VCAM-1 alone is not sufficient for lesion formation.
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