Abstract
Diabetes is a risk factor for development of atherosclerotic cardiovascular disease. Animal model studies in mice revealed that hyperglycemia increases development of atherosclerosis in the aorta as well as myocardial fibrosis in surgical models of coronary artery ligation; however, the impact of hyperglycemia on coronary artery atherosclerosis and subsequent heart disease is less clear. To investigate the effect of hyperglycemia on atherosclerosis and coronary heart disease, we used a mouse model of diet-induced coronary artery atherosclerosis and myocardial infarction, the high fat/high cholesterol (HFC) diet fed SR-B1 knockout (KO)/apoE-hypomorphic (HypoE) mouse. Hyperglycemia was induced in these mice by streptozotocin (STZ) treatment. This increased HFC diet-dependent atherosclerosis development (p = 0.02) and necrotic core formation (p = 0.0008) in atherosclerotic plaques in the aortic sinus but did not increase the extent of atherosclerosis in coronary arteries. However, it did increase the extent of platelet accumulation in atherosclerotic coronary arteries (p = 0.017). This was accompanied by increased myocardial fibrosis (p = 0.005) and reduced survival (p = 0.01) compared to control-treated, normoglycemic mice. These results demonstrate that STZ-treatment exerted differential effects on the level of atherosclerosis in the aortic sinus and coronary arteries. These results also suggest that SR-B1-KO/HypoE mice may be a useful non-surgical model of diabetic cardiomyopathy in the context of coronary artery atherothrombosis.
Highlights
Type I diabetes patients present an increased risk of developing cardiovascular diseases relative to the general population (de Ferranti et al, 2014)
Taking advantage of the inducible nature of the coronary artery atherosclerosis and myocardial infarction in scavenger receptor class b type 1 (SR-B1)-KO/hypomorphic mutant apoE allele (hypoE) mice, we tested whether the induction of hyperglycemia in these mice affected the development of the diet induced coronary heart disease phenotype
We report that multiple low dose STZ-treatment was not sufficient to induce coronary artery atherosclerosis in SR-B1-KO/hypoE mice fed a normal low fat/low cholesterol diet, and did not increase the extent of high fat/high cholesterol (HFC) diet induced coronary artery atherosclerosis
Summary
Type I diabetes patients present an increased risk of developing cardiovascular diseases relative to the general population (de Ferranti et al, 2014). The effects of hyperglycemia on coronary artery atherosclerosis are less well-studied, in part because conventional mouse atherosclerosis models, such as apolipoprotein E (apoE) or LDLR deficient mice, do not develop substantial coronary artery atherosclerosis or subsequent myocardial infarction (Gonzalez et al, 2016; Trigatti and Fuller, 2016). Mice deficient in the HDL receptor, SR-B1, exhibit substantially increased HDL cholesterol as a result of impaired hepatic HDL cholesterol clearance (Rigotti et al, 1997). Mice deficient in both SR-B1 and apo E, SR-B1/apoE double KO mice, exhibit accelerated aortic sinus atherosclerosis development (Trigatti et al, 1999) as well as spontaneous development of extensive, occlusive atherosclerosis in coronary arteries, myocardial infarction, and early death (∼6–8 weeks of age; Braun et al, 2002). Taking advantage of the inducible nature of the coronary artery atherosclerosis and myocardial infarction in SR-B1-KO/hypoE mice, we tested whether the induction of hyperglycemia in these mice affected the development of the diet induced coronary heart disease phenotype
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