Diet-Induced Occlusive Coronary Atherosclerosis, Myocardial Infarction, Cardiac Dysfunction, and Premature Death in Scavenger Receptor Class B Type I-Deficient, Hypomorphic Apolipoprotein ER61 Mice

Abstract

Background-Normal chow (low fat)-fed mice deficient in both the HDL receptor SR-BI and apolipoprotein E (SR-BI/apoE dKO) provide a distinctive model of coronary heart disease (CHD). They exhibit early-onset hypercholesterolemia characterized by unesterified cholesterol-rich abnormal lipoproteins (lamellar/vesicular and stacked discoidal particles), occlusive coronary atherosclerosis, spontaneous myocardial infarction, cardiac dysfunction, and premature death (Ϸ6 weeks of age). Mice in which similar features of CHD could be induced with a lipid-rich diet would represent a powerful tool to study CHD. Methods and Results-To generate a diet-inducible model of CHD, we bred SR-BI-deficient (SR-BI KO) mice with hypomorphic apolipoprotein E mice (ApoeR61 h/h ) that express reduced levels of an apoE4-like murine apoE isoform and exhibit diet-induced hypercholesterolemia. When fed a normal chow diet, SR-BI KO/ApoeR61 h/h mice did not exhibit early-onset atherosclerosis or CHD; the low expression level of the apoE4-like murine apoE was atheroprotective and cardioprotective. However, when fed an atherogenic diet rich in fat, cholesterol, and cholate, they rapidly developed hypercholesterolemia, atherosclerosis, and CHD, a response strikingly similar to that of SR-BI/apoE dKO mice fed a chow diet, and they died 32Ϯ6 days (50% mortality) after initiation of the high-fat feeding. Conclusions-The SR-BI KO/ApoeR61h/h mouse is a new model of diet-induced occlusive coronary atherosclerosis and CHD (myocardial infarction, cardiac dysfunction and premature death), allowing control of the age of onset, duration, severity, and possibly regression of disease. Thus, SR-BI KO/ApoeR61 h/h mice have the potential to contribute to our understanding of CHD and its prevention and treatment.

Hepatic Lipase Deficiency Delays Atherosclerosis, Myocardial Infarction, and Cardiac Dysfunction and Extends Lifespan in SR-BI/Apolipoprotein E Double Knockout Mice

“…SR-BI KO/ApoeR61 h/h mice have low, rather than no, plasma apoE, rendering them susceptible to diet-induced hyperlipidemia, atherosclerosis and CHD. 23,46 Taken together with our earlier studies, [2][3][4]21 this work supports the suggestion that occlusive coronary atherosclerosis is directly responsible for ischemia-induced myocardial infarction, which in turn leads to cardiac dysfunction and premature death, a pathologic process closely resembling that in human CHD. Because rapid onset occlusive coronary arterial atherosclerosis, (to date, occlusive thrombi have not been observed in these mice [unpublished data, 2005]), associated MI does not usually accompany the aortic atherosclerosis seen in other common murine models of hyperlipidemia, 24,47-51 the dKO mouse, and its variant, SR-BI KO/ ApoeR61 h/h mice, 23 provide attractive small animal models of human occlusive atherosclerotic CHD for genetic and pharmacological studies of the mechanisms underlying the most common causes of heart disease and preclinical testing of new therapeutic strategies.…”

“…As previously reported, higher lipoprotein surface to core lipid ratios are associated with greater atherogenic potential in different SR-BI-deficient models of CHD. 4,23 Thus, we did not observe substantial HL-dependent differences in the lipoproteins. Further studies are necessary to determine whether subtle differences in lipoprotein structures caused by HL deficiency, or if HL-dependent changes in lipoprotein metabolism distinct from changes in particle structure (eg, as a consequence of the lipoprotein binding activity of HL), 29 were responsible for the striking effects on atherosclerosis in dKO mice.…”

“…3 It and its variant, the SR-BI KO/ApoeR61 h/h mouse, 23 provide uniquely powerful tools to investigate the mechanisms underlying CHD and to identify potential therapeutic targets and approaches. For their promise to be realized, it is necessary to determine whether the CHD etiology and pathology in these models are similar to those in humans.…”

“…Hearts from tKO-6 mice were similar in surface appearance to CHD-free control hearts ( Figure 3A and 3C), whereas those from dKO-6s and tKO-9s were markedly enlarged and exhibited surface patches characteristic of large MIs 3 ( Figure 3B and 3D). Although the heart-to-body weight ratio for tKO-6s was significantly larger than that for controls (1.3-fold), indicating that the tKO-6 hearts were not normal; this cardiomegaly, caused at least in part by hypertrophy, 23 was significantly less than that of dKO-6s (1.9-fold) or tKO-9s (1.7-fold) ( Figure 3E). Masson's trichrome 3 stained longitudinal heart sections ( Figure 4A to 4C, healthy myocardium stains red, fibrotic tissue blue) showed that, unlike the massive fibrosis/MI present in virtually all dKO-6 and tKO-9 hearts (Figures 4A and 4C), with especially marked left ventricular dilation and fibrosis in the outflow tracts of the most ill tKO-9s, tKO-6 hearts were relatively healthy, with little fibrosis ( Figure 4B) or intramyocardial neutral lipid deposition 3 (Oil Red O staining, data not shown).…”

Severely altered cholesterol homeostasis in macrophages lacking apoE and SR-BI

“…Numerous studies have demonstrated that both SR-BI and apoE are important in minimizing atherosclerotic lesion development. Single-gene deletion of either apoE (7,8) or SR-BI (9) in mice accelerates atherosclerotic lesion development, whereas low-level transgenic expression of either SR-BI (3) or apoE (10,11) reduces the extent of atherosclerosis. Furthermore, the combined deficiency of SR-BI and apoE produces the only mouse model of accelerated and fatal atherosclerosis.…”