Effect of hyperglycemia and hyperlipidemia on atherosclerosis in LDL receptor-deficient mice: establishment of a combined model and association with heat shock protein 65 immunity.

Keren, Pnina; George, Jacob; Shaish, Aviv; Levkovitz, Hana; Janakovic, Zora; Afek, Arnon; Goldberg, Iris; Kopolovic, Juri; Keren, Gad; Harats, Dror

doi:10.2337/diabetes.49.6.1064

Cited by 57 publications

(42 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The effect of dyslipidemia in relation to other conditions associated with diabetes (e.g., hyperglycemia) on lesion initiation has not been addressed previously because of the lack of suitable animal models. In existing models, the effects of diabetesinduced increases in cholesterol, triglyceride, and blood glucose levels have been difficult to separate (8)(9)(10)(11)(12)(13)(14). In the LDLR -/-;GP model used here, not only is the mechanism of diabetes induction more similar to that in humans than previous models that used the toxins streptozotocin or alloxan, but, importantly, these mice do not develop diabetes-induced lipid abnormalities when fed a cholesterol-free diet.…”

Section: Diabetes In the Absence Of Dyslipidemia Secondary To Diabetementioning

confidence: 80%

Diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions

et al. 2004

View full text Add to dashboard Cite

Diabetes in humans accelerates cardiovascular disease caused by atherosclerosis. The relative contributions of hyperglycemia and dyslipidemia to atherosclerosis in patients with diabetes are not clear, largely because there is a lack of suitable animal models. We therefore have developed a transgenic mouse model that closely mimics atherosclerosis in humans with type 1 diabetes by breeding low-density lipoprotein receptor-deficient mice with transgenic mice in which type 1 diabetes can be induced at will. These mice express a viral protein under control of the insulin promoter and, when infected by the virus, develop an autoimmune attack on the insulin-producing β cells and subsequently develop type 1 diabetes. When these mice are fed a cholesterol-free diet, diabetes, in the absence of associated lipid abnormalities, causes both accelerated lesion initiation and increased arterial macrophage accumulation. When diabetic mice are fed cholesterol-rich diets, on the other hand, they develop severe hypertriglyceridemia and advanced lesions, characterized by extensive intralesional hemorrhage. This progression to advanced lesions is largely dependent on diabetes-induced dyslipidemia, because hyperlipidemic diabetic and nondiabetic mice with similar plasma cholesterol levels show a similar extent of atherosclerosis. Thus, diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions.

show abstract

Section: Diabetes In the Absence Of Dyslipidemia Secondary To Diabetementioning

confidence: 80%

Diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions

et al. 2004

View full text Add to dashboard Cite

show abstract

“…The disease was independent of changes in plasma lipid levels. Because on the HCD, diabetes markedly increased plasma cholesterol, as was noted in other models (5,8), the smaller lesions in nondiabetic animals probably reflected their relatively lower circulating lipid levels. Overall, the data suggest that hAR mediates toxic effects on the blood vessel only in the presence of hyperglycemia.…”

Section: Figurementioning

confidence: 92%

Human aldose reductase expression accelerates diabetic atherosclerosis in transgenic mice

Vikramadithyan

Hu²,

Noh³

et al. 2005

Journal of Clinical Investigation

161

155

View full text Add to dashboard Cite

Direct evidence that hyperglycemia, rather than concomitant increases in known risk factors, induces atherosclerosis is lacking. Most diabetic mice do not exhibit a higher degree of atherosclerosis unless the development of diabetes is associated with more severe hyperlipidemia. We hypothesized that normal mice were deficient in a gene that accelerated atherosclerosis with diabetes. The gene encoding aldose reductase (AR), an enzyme that mediates the generation of toxic products from glucose, is expressed at low levels in murine compared with human tissues. Mice in which diabetes was induced through streptozotocin (STZ) treatment, but not nondiabetic mice, expressing human AR (hAR) crossed with LDL receptor-deficient (Ldlr -/-) C57BL/6 male mice had increased aortic atherosclerosis. Diabetic hAR-expressing heterozygous LDL receptor-knockout mice (Ldlr +/-) fed a cholesterol/cholic acid-containing diet also had increased aortic lesion size. Lesion area at the aortic root was increased by STZ treatment alone but was further increased by hAR expression. Macrophages from hARtransgenic mice expressed more scavenger receptors and had greater accumulation of modified lipoproteins than macrophages from nontransgenic mice. Expression of genes that regulate regeneration of glutathione was reduced in the hAR-expressing aortas. Thus, hAR increases atherosclerosis in diabetic mice. Inhibitors of AR or other enzymes that mediate glucose toxicity could be useful in the treatment of diabetic atherosclerosis. IntroductionAlthough people with both type 1 and type 2 diabetes develop increased atherosclerosis, which leads to more heart attacks and strokes, direct evidence that this is mediated by hyperglycemia is lacking. In part, this is because additional atherogenic factors such as lipid abnormalities and hypertension accompany the diabetes (1, 2). Efforts to demonstrate the presumed toxic effects of hyperglycemia in experimental animals have been similarly hindered (3). Diabetes has been superimposed onto wild-type and atherosclerosis-prone mice in an attempt to reproduce the relationship between diabetes and macrovascular disease. However, a clear model of diabetes-induced accelerated atherosclerosis is lacking. In several situations, genetic insulin resistance and streptozotocin-mediated (STZ-mediated) destruction of islet cells produced greater hyperlipidemia and, not surprisingly, more atherosclerosis (4). This was noted in both LDL receptorknockout (Ldlr -/-) (5, 6) and apoE-knockout mice (7). In a recent study, chow-fed Ldlr -/-diabetic mice had more atherosclerosis at the aortic root, but when these mice were fed cholesterol-containing diet, the atherosclerosis correlated with plasma cholesterol and not glucose (8). Thus, as in many previous reports, the more advanced vascular lesions in these mice were attributable to greater hyperlipidemia and not hyperglycemia or defective insulin actions.

show abstract

“…LDL receptor knockout mice often more than double their plasma cholesterol in the setting of islet destruction 58,59 or deficiency of leptin actions. 60,61 The reasons for this are not known but might reflect reduced clearance pathways through LDL receptor-related protein (LRP) and/or scavenger receptors, increased lipoprotein production caused by changes in apoB production associated with intrahepatic signaling 62 or fatty acid rescue of apoB from degradation, 63 increased MTP expression, 64 or greater ingestion of the atherogenic diet.…”

Section: How Does Diabetes Change Lipoprotein Metabolism In Humans Anmentioning

confidence: 99%

“…92 In other studies diabetic LDL receptor knockout mice developed more lesions associated with a marked increase in plasma cholesterol. 58 A recent paper described experiments in which early lesions in chow fed mice were increased with viral destruction of the pancreatic islets. 59 However, with a diet containing cholesterol and fat, diabetic mice had much greater levels of blood lipids, and a distinct effect of diabetes, rather than hyperlipidemia, was no longer apparent.…”

Section: The Apob Transgenics Do Not Normally Develop Diabetes-inducementioning

confidence: 99%

Diabetic Vascular Disease

Goldberg

Dansky

2006

ATVB

View full text Add to dashboard Cite

Abstract-It is well known that humans with diabetes have more atherosclerosis and its complications. The causes of this relationship are, however, unclear. Although recent data show that improved glycemic control reduces arterial disease in type 1 diabetes, other studies have shown that subjects with "prediabetes" have more cardiovascular disease before the development of hyperglycemia. Thus, either hyperglycemia and/or lack of insulin actions are toxic to arteries, or metabolic derangements exclusive of hyperglycemia are atherogenic. For Ͼ50 years animal models of diabetes and atherosclerosis have been used to uncover potential mechanisms underlying diabetes associated cardiovascular disease. Surprisingly, diabetes alone increases vascular disease in only a few select animal models. Increased atherosclerosis has been found in several animals and lines of genetically modified mice; however, diabetes often also leads to greater hyperlipidemia. This makes it difficult to separate the toxic effects of insulin lack and/or hyperglycemia from those caused by the lipids. These studies are reviewed, as well as more recent investigations using new methods to create diabetic-atherosclerotic models.

show abstract

Effect of hyperglycemia and hyperlipidemia on atherosclerosis in LDL receptor-deficient mice: establishment of a combined model and association with heat shock protein 65 immunity.

Cited by 57 publications

References 28 publications

Diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions

Diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions

Human aldose reductase expression accelerates diabetic atherosclerosis in transgenic mice

Diabetic Vascular Disease

Contact Info

Product

Resources

About