Abstract
BackgroundLack of suitable mouse models has hindered the studying of diabetic macrovascular complications. We examined the effects of type 2 diabetes on coronary artery disease and cardiac function in hypercholesterolemic low-density lipoprotein receptor-deficient apolipoprotein B100-only mice (LDLR-/-ApoB100/100).Methods and results18-month-old LDLR-/-ApoB100/100 (n = 12), diabetic LDLR-/-ApoB100/100 mice overexpressing insulin-like growth factor-II (IGF-II) in pancreatic beta cells (IGF-II/LDLR-/-ApoB100/100, n = 14) and age-matched C57Bl/6 mice (n = 15) were studied after three months of high-fat Western diet. Compared to LDLR-/-ApoB100/100 mice, diabetic IGF-II/LDLR-/-ApoB100/100 mice demonstrated more calcified atherosclerotic lesions in aorta. However, compensatory vascular enlargement was similar in both diabetic and non-diabetic mice with equal atherosclerosis (cross-sectional lesion area ~60%) and consequently the lumen area was preserved. In coronary arteries, both hypercholesterolemic models showed significant stenosis (~80%) despite positive remodeling. Echocardiography revealed severe left ventricular systolic dysfunction and anteroapical akinesia in both LDLR-/-ApoB100/100 and IGF-II/LDLR-/-ApoB100/100 mice. Myocardial scarring was not detected, cardiac reserve after dobutamine challenge was preserved and ultrasructural changes revealed ischemic yet viable myocardium, which together with coronary artery stenosis and slightly impaired myocardial perfusion suggest myocardial hibernation resulting from chronic hypoperfusion.ConclusionsLDLR-/-ApoB100/100 mice develop significant coronary atherosclerosis, severe left ventricular dysfunction with preserved but diminished cardiac reserve and signs of chronic myocardial hibernation. However, the cardiac outcome is not worsened by type 2 diabetes, despite more advanced aortic atherosclerosis in diabetic animals.
Highlights
Lack of suitable mouse models has hindered the studying of diabetic macrovascular complications
To study the cardiac phenotype of hypercholesterolemic low density lipoprotein receptor (LDLR)-/-ApoB100/100 mice and to see if it is impaired by diabetes, we evaluated the extent of coronary artery disease (CAD) and its effects on myocardial perfusion, left ventricular function and cardiac reserve in vivo
It did not reflect on other metabolic factors such as blood glucose or glucose tolerance - the insulin-like growth factorII (IGF-II)/LDLR-/-ApoB100/100 mice showed both fasting hyperglycemia (8.2 ± 3.0 mmol/l) and impaired glucose tolerance in intraperitoneal Glucose tolerance test (GTT) (2-hour post-glucose load 14.7 ± 6.0 mmol/l) compared to LDLR-/-ApoB100/100 and C57Bl/6J mice (Table 1 Figure 1)
Summary
Lack of suitable mouse models has hindered the studying of diabetic macrovascular complications. Achieving models representing the overall metabolic changes typical for diabetic patients with the highest risk of macrovascular complications has mostly been pursued by cross-breeding leptin-deficient (ob/ob) or leptin receptor-deficient (db/db) mice with atherosclerotic ApoE-/- [9,10,11] and LDLR-/- [9,12] mice. A major shortcoming in these models is that the perturbation of glucose metabolism does not appear to affect atherosclerosis without concomitant elevations in plasma lipid levels [14,15] Data about their cardiac phenotype is scarce - there are only a few studies on ventricular function of ob/ob/LDLR-/- mice [16,17,18], differentiating the effects of diabetes from those of hypercholesterolemia cannot be done without comparisons to non-diabetic hypercholesterolemic mice. The status of coronary artery atherosclerosis and its relation to cardiac function have not been studied in any comparable models of diabetic macrovascular disease
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