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Circulation Research. 2002;90:244-245

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(Circulation Research. 2002;90:244.)
© 2002 American Heart Association, Inc.

Editorials

MIghty Mouse

Alan R. Tall

From the Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY.

Correspondence to Alan R. Tall, Division of Molecular Medicine, Dept of Medicine, Columbia University, New York, NY 10032. E-mail art1{at}columbia.edu


Key Words: atherosclerosis • myocardial infarction • mouse • scavenger receptor-BI

A mouse with spontaneous coronary atherosclerosis and myocardial infarction (MI) would be a wonderful research tool. In this issue of Circulation Research, Braun et al1 show that young mice with combined deficiencies of apolipoprotein E (apoE) and the scavenger receptor-BI (SR-BI) spontaneously develop severe coronary atherosclerosis, myocardial infarction, and cardiac dysfunction. Although much remains to be learned about the underlying mechanisms, it is clear that this study represents an important step toward developing an authentic mouse model of coronary occlusion and human myocardial infarction. These animals are likely to be useful for studying the effects of genetic or other interventions on these disease processes.

SR-BI was originally identified by expression cloning and shown to bind both native and modified LDL.2 Insightfully, Krieger and colleagues3 then showed that SR-BI can also bind HDL and mediate the selective cellular uptake of HDL cholesteryl ester without degradation of HDL protein, ie, selective uptake. Selective uptake of HDL cholesteryl esters in tissues had been described more than a decade earlier by lipoprotein physiologists who showed that the process was most active in rodent liver and adrenals.4 These organs are also the principal sites of SR-BI expression, and mice with decreased SR-BI expression have increased HDL levels5,6 and decreased selective uptake.6 When crossed with apoE7 or LDL receptor knockout (KO) mice,8 the SR-BI deficient mice were found to have increased atherosclerosis in the aortic root. Conversely, mice with hepatic overexpression of SR-BI tended to have reduced HDL levels and diminished aortic atherosclerosis.9,10

In the present study, Braun et al1 noticed that SR-BI/apoE double KO mice were dying at a young age. Suspecting that the animals might be suffering from heart disease, they carried out a careful analysis of cardiac pathology and function in 4- to 6-week-old mice. This revealed severe coronary artery occlusive disease, associated with lipid and fibrin deposition, extensive areas of myocardial infarction and fibrosis, and increased heart weight. Functional studies showed reduced cardiac contractility, reduced ejection fraction, diminished arterial blood pressure, and the development of cardiac arrhythmias during anesthesia. Thus, it appears that severe occlusive coronary disease has caused myocardial infarction and diminished cardiac function.

These striking findings are not completely without precedent. Chow-fed apoE KO mice develop mild coronary atherosclerosis at 6 to 8 months old as well as patchy myocardial fibrosis,11 but the cardiac pathology is not nearly as striking as seen here. ApoE/LDL receptor double KO mice or apoE KO mice fed a high-fat, high-cholesterol diet develop severe occlusive coronary disease and myocardial infarction and are susceptible to stress-induced coronary ischemia and myocardial infarction.12 The coronary pathology in these animals appears similar to that described herein, but apparently develops much more slowly. Total plasma cholesterol levels in these mice are usually >1500 versus 700 to 800 mg/dL in the SR-BI/apoE double KO mice.7 The present study lacked a control group of isogenic apoE KO mice fed a high-fat diet to match total plasma cholesterol levels with the chow-fed SR-BI/apoE double KO animals. However, based on a comparison with the earlier study,7 it seems likely that SR-BI deficiency contributes in a special way to the florid coronary atherosclerosis, independent of its effects on total plasma cholesterol levels.

There are a number of potential atherogenic mechanisms in SR-BI deficiency, but the relative contribution of each of these is unknown. In the absence of apoE or LDL receptors, SR-BI has a role in determining VLDL and LDL cholesterol levels, and in some studies this appears to be an important factor accounting for its effects on atherogenesis.8 However, in the present study, it is highly likely that increased coronary atherosclerosis is disproportionate to increased VLDL and LDL cholesterol levels. SR-BI deficiency results in the accumulation of cholesteryl ester–enriched HDL particles. These particles are so large they accumulate within the IDL or VLDL size range. Although elevated HDL is usually considered to be protective, in SR-BI KO mice, this might be detrimental because it results from a block in the transport of HDL cholesterol into the liver and bile. SR-BI plays an important role in the clearance of HDL-free and esterified cholesterol in the liver and the transport of cholesterol into bile.13 By selective removal of HDL lipids in the liver, SR-BI may help to regenerate lipid-poor HDL species that act as preferential substrates for ABCA1 in macrophage foam cells.14 ABCA1, the defective molecule in Tangier Disease,15–17 plays an essential role in the efflux of cholesterol and phospholipids to lipid-poor apolipoproteins.18 Thus, the action of SR-BI in the liver could have important antiatherogenic effects at the level of the macrophage foam cell, although hepatic overexpression of SR-BI is not associated with an overall increase in cholesterol flow from the periphery to the liver.19 SR-BI itself also facilitates free cholesterol efflux from cells and could directly contribute to cholesterol efflux from macrophage foam cells.20 SR-BI in endothelium may have a role in HDL-stimulated NO release, and this could be of potential importance in the coronary vasculature.21 In summary, a number of different antiatherogenic effects of SR-BI have been described, but the relative importance of these or other unsuspected mechanisms in the evolution of coronary atherosclerosis awaits further clarification.

Although this study1 and that of Hansson and coworkers12 describe useful models of occlusive coronary artery disease that potentially can be used for preclinical drug or gene testing, these models still appear to be fundamentally different to the common form of human coronary occlusion, in which a cracked or eroded plaque is associated with an occluding thrombus. It is notable that neither study presented evidence of organizing thrombus or plaque rupture. Although intraplaque hemorrhages have been described in the innominate artery of apoE knockout mice at an advanced age,22 these lesions also do not resemble human coronary thrombotic occlusion. Attempts to achieve plaque rupture by macrophage-specific overexpression of metalloproteases have so far failed.22 Thus, an authentic mouse model of plaque rupture and thrombosis leading to myocardial infarction has yet to be attained. This could be because of intrinsic differences in the clotting system, metalloprotease/metalloprotease inhibitors, or hemodynamics of coronary vessels in mice. Finally, it should be noted that although human SR-BI is expressed in similar tissues as in mice,23 no human genetic deficiency of SR-BI has yet been described. The present study suggests that such a condition would have an unusual clinical presentation with elevated HDL levels and severe premature coronary artery disease.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

  1. Braun A, Trigatti BL, Post MJ, Sato K, Simons M, Edelberg JM, Rosenberg RD, Schrenzel M, Krieger M. Loss of SR-BI expression leads to the early onset of occlusive atherosclerotic coronary artery disease, spontaneous myocardial infarctions, severe cardiac dysfunction, and premature death in apolipoprotein E–deficient mice. Circ Res. 2002; 90: 270–276.[Abstract/Free Full Text]
  2. Acton SL, Scherer PE, Lodish HF, Krieger M. Expression cloning of SR-BI, a CD36-related class B scavenger receptor. J Biol Chem. 1994; 269: 21003–21009.[Abstract/Free Full Text]
  3. Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science. 1996; 271: 518–520.[Abstract]
  4. Glass C, Pittman RC, Weinstein DB, Steinberg D. Dissociation of tissue uptake of cholesterol ester from that of apoprotein A-I of rat plasma high density lipoprotein: selective delivery of cholesterol ester to liver, adrenal, and gonad. Proc Natl Acad Sci U S A. 1983; 80: 5435–5439.[Abstract/Free Full Text]
  5. Rigotti A, Trigatti BL, Penman M, Rayburn H, Herz J, Krieger M. A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its key role in HDL metabolism. Proc Natl Acad Sci U S A. 1997; 94: 12610–12615.[Abstract/Free Full Text]
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  13. Ji Y, Wang N, Ramakrishnan R, Sehayek E, Huszar D, Breslow JL, Tall AR. Hepatic scavenger receptor BI promotes rapid clearance of high density lipoprotein free cholesterol and its transport into bile. J Biol Chem. 1999; 274: 33398–33402.[Abstract/Free Full Text]
  14. Wang N, Silver DL, Costet P, Tall AR. Specific binding of ApoA-I, enhanced cholesterol efflux, and altered plasma membrane morphology in cells expressing ABC1. J Biol Chem. 2000; 275: 33053–33058.[Abstract/Free Full Text]
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