Diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions
Catherine B. Renard, … , Alan Chait, Karin E. Bornfeldt
Catherine B. Renard, … , Alan Chait, Karin E. Bornfeldt
Published September 1, 2004
Citation Information: J Clin Invest. 2004;114(5):659-668. https://doi.org/10.1172/JCI17867.
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Diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions

Abstract

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.

Authors

Catherine B. Renard, Farah Kramer, Fredrik Johansson, Najib Lamharzi, Lisa R. Tannock, Matthias G. von Herrath, Alan Chait, Karin E. Bornfeldt

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Diabetes caused advanced lesions in mice fed cholesterol-rich diets. Dia...
Diabetes caused advanced lesions in mice fed cholesterol-rich diets. Diabetic LDLR–/–;GP mice fed the 0.12% cholesterol diet (A, B, and E), or 0.5% cholesterol diet (C), and nondiabetic LDLR–/–;GP littermates fed the 0.12% cholesterol diet (F) or the 0.5% cholesterol diet (D) were perfusion fixed after 12 weeks on diet, as described in Figure 4. The BCA was dissected, paraffin embedded, and serial sectioned until maximal lesion size was identified. Sections were stained using a Movat’s pentachrome procedure (A–D). Black represents nuclei and elastin, yellow represents collagen and reticular fibers, blue represents glycosaminoglycans, red represents muscle, and intense red represents fibrinoid and fibrin (hemorrhage). Some sections were used to detect AGEs (E and F). Representative sections are shown. Note the intralesional hemorrhage (marked by arrows) in A and C. In B, erythrocytes in the lesion are indicated by open arrows. Scale bars: 100 μm (A, C–F); 20 μm (B). (G) A graphical representation of frequency of hemorrhage in lesions of similar size from diabetic and nondiabetic mice.