Evidence of extensive atherosclerosis, coronary artery disease and myocardial infarction in the ApoE −/−:Ins2 +/Akita mouse fed a western diet

BACKGROUND AND AIMS: Diabetic patients with no history of cardiac infarction have a prevalence of coronary atherosclerosis and a risk of heart attack equivalent to euglycemic patients who have coronary atherosclerosis and have suffered a prior myocardial infarction. Although several murine models of diabetes have been established, none of these show indications of cardiac events. In an attempt to establish a diabetic mouse model with coronary atherosclerosis and myocardial injury, we have fed hyperglycemic ApoE^-/-:Ins2^+/Akita mice a western diet to enhance the dyslipidemic phenotype. METHODS: Five-week-old ApoE^-/-:Ins2^+/Akita mice and ApoE^-/- controls were fed a diet, 0.15% cholesterol and 21% anhydrous milk lipids, until 25 weeks of age. Changes in lifespan, clinical and metabolic parameters were evaluated as well as atherosclerosis and heart injury. RESULTS: In comparison to male ApoE^-/-, male ApoE^-/-:Ins2^+/Akita mice presented with chronic hyperglycemia (30.8 ± 1.2 mM vs. 9.3 ± 0.5 mM) accompanied by extremely high levels of total plasma cholesterol (49.3 ± 6.3 mM vs. 30.1 ± 1.5 mM) and triglycerides (11.6 ± 1.7 mM vs. 2.36 ± 0.18 mM). These mice have atherosclerosis at multiple vascular sites, including aortic sinus, ascending and descending aorta, brachiocephalic artery and coronary arteries. In addition, myocardial infarcts and a significant reduction of the lifespan (close to 20% of survival vs. other groups) were observed. Distinctively, both strains of female mice presented a parallel increase in plasma lipids, atherosclerosis, and no effects on mortality. CONCLUSIONS: We have established a diabetic mouse model, the western-diet-fed male ApoE^-/-:Ins2^+/Akita mouse, with profound cardiovascular disease involving extensive atherosclerosis, coronary artery disease and myocardial infarct resulting in shortened lifespan.