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
Murine models of atherosclerosis, such as the apolipoprotein E (apoE) or the LDL receptor knockout mice, usually do not exhibit many of the cardinal features of human coronary heart disease (CHD), eg, spontaneous myocardial infarction, severe cardiac dysfunction, and premature death. Here we show that mice with homozygous null mutations in the genes for both the high density lipoprotein receptor SR-BI and apoE (SR-BI/apoE double knockout [dKO] mice) exhibit morphological and functional defects with similarities to those seen in human CHD. When fed a standard chow diet, these hypercholesterolemic animals developed significant atherosclerotic lesions in the aortic sinus as early as 4 to 5 weeks after birth. We now show that they also exhibited extensive lipid-rich coronary artery occlusions and spontaneously developed multiple myocardial infarctions and cardiac dysfunction (eg, enlarged hearts, reduced ejection fraction and contractility, and ECG abnormalities). Their coronary arterial lesions, which were strikingly similar to human atherosclerotic plaques, exhibited evidence of cholesterol clefts and extensive fibrin deposition, indicating hemorrhage and clotting. All of the dKO mice died by 8 weeks of age (50% mortality at 6 weeks). Thus, SR-BI/apoE dKO mice provide a new murine model for CHD and may help better define the role of lipoprotein metabolism and atherosclerosis in the pathogenesis of myocardial infarction and cardiac dysfunction. Furthermore, these animals may be useful for preclinical testing of potential genetic and/or pharmacological therapies for CHD.
- SR-BI/apolipoprotein E knockout mice
- myocardial infarction
- coronary artery disease
- lipoprotein metabolism
One of the best understood risk factors for coronary artery atherosclerosis, a leading cause of myocardial infarction (MI) and death, is hypercholesterolemia. Unfortunately, few hypercholesterolemia and atherosclerosis rodent models spontaneously develop MIs and cardiac dysfunction. Fat-fed LDL receptor (LDLR) knockout (KO)1 and chow-fed apolipoprotein E (apoE) KO mice,2–4⇓⇓ standard models for hypercholesterolemia/atherosclerosis, do not usually exhibit MI or reduced lifespans; although 24- to 40-week-old, fat-fed apoE KO mice can develop coronary arterial plaques and, occasionally, small areas of myocardial fibrosis.4,5⇓ ApoE/LDLR double KO mice fed a high-fat/high-cholesterol diet for 7 months have occlusive coronary arterial atherosclerotic lesions and some associated perivascular myocardial scarring.6 Severe stress exacerbates the small ECG abnormalities seen in these mice at rest and can induce endothelin-dependent MIs,6 although such MIs were not reported to be lethal. Dahl salt-sensitive, hypertensive rats expressing high levels of human cholesteryl ester transfer protein7 and atherosclerosis-prone male JCR:LA-corpulent rats,8 which have hyperlipidemia and atherosclerosis, develop coronary artery lesions and MIs.
It would be useful to have additional, genetically manipulable, murine models of coronary heart disease (CHD) that combine many of the cardinal features of human cardiovascular disease, including hypercholesterolemia, atherosclerosis, occlusive fibrin-rich coronary artery lesions, ischemia, MIs, and cardiac dysfunction. We now report that double knockout (dKO) mice with homozygous null mutations in the apoE and the HDL receptor scavenger receptor class B, type I (SR-BI) genes, which exhibit hypercholesterolemia and dramatically accelerated atherosclerosis,9 spontaneously develop extensive lipid- and fibrin-rich occlusive coronary arterial lesions, multiple MIs, and cardiac dysfunction and die prematurely at ≈6 weeks of age. Thus, SR-BI/apoE dKO mice represent a new model for the study of CHD.
Materials and Methods
Mice (mixed C57BL/6x129 background) were generated at MIT and were housed and fed a normal chow diet as previously described.9,10⇓ All experiments were performed in accordance with proper guidelines for the care and use of laboratory animals and were subject to prior approval by the Committee on Animal Care at MIT. Genotypes were determined as described previously.9,10⇓ Unless otherwise noted, 4- to 6-week old dKO mice, apoE KO littermates, and SR-BI KO and wild type controls on the same background were studied. No significant differences were observed between males and females.
Mice were euthanized and tissues prepared for cryosectioning as previously described.9 Tissues for paraffin sections were immersion-fixed in buffered 10% formalin (J.T. Baker). Sometimes heparin was administered (450 U/20 g, IV) prior to euthanasia to prevent coagulation.11 Tissue sections were stained with Masson’s trichrome (Sigma), 12 hematoxylin, and eosin (H&E) or Oil red O and hematoxylin.9 Immunohistochemistry was performed using anti-fibrin (NYB-T2G1, 1 μg/mL, Accurate Chemical & Scientific Corp) or anti-macrophage (F4/80, MCA 497, Serotec, diluted 1:10) antibodies using M.O.M. immunodetection (AEC substrate) or Vectastain Elite ABC (diaminobenzidine substrate) kits (Vector), respectively, with hematoxylin counter-staining.
Mice were euthanized, weighed, and perfused,9 and intact hearts or the right ventricular (RV) free wall and the left ventricle (LV)+septum (LV+S) were dissected and weighed.
Magnetic Resonance Imaging (MRI)
Mice were anesthetized (chloral hydrate, 200 to 320 mg/kg IP; Sigma) and placed in a 2T small bore magnet (Bruker Instruments) on a custom body coil containing ECG electrode patches. Heart rates were adjusted to ≈300 bpm with 1% to 2% isoflurane. Scout, long-axis, and 6 to 7 1-mm thick short-axis images were collected. Short-axis images spanning the entire heart were used to measure LV tissue volume, LV end diastolic and end systolic luminal volumes (LVEDV and LVESV), and ejection fractions (EF=((LVEDV−LVESV)/LVEDV)×100%).
Mice were heparinized (1 U/10 g IP), anesthetized with chloral hydrate as above, intubated, and ventilated (Harvard Apparatus, Inc) with room air (130 breaths/min; tidal volume: ≈15 μL/g). Lidocaine HCl (0.5%; Abbott) was administered locally. The right carotid artery was exposed and a 1.4 Fr micromanometer catheter (Millar Instruments) was advanced into the aorta and then the LV for pressure measurements. LV pressures were measured before and after cutting both vagal nerves. Data were recorded using a Windaq DI 220 converter and analyzed using Windaq Pro software (Dataq Instrument) with some manual intervention to correct for micromanometer drift and insure proper evaluation of LVEDP.
After median sternotomy, cannulation of the ascending aorta (PE50 polyethylene tubing: Becton Dickinson and Company), and opening the right atrium for drainage, each heart was harvested, flushed with PBS, and barium sulfate (E-Z-EM, Inc) was injected manually at a maximum pressure of 80 mm Hg. Angiograms were obtained with a Micro 50 (General Electric, 20 kV, 20-second exposure). Only the left coronary arterial network could be routinely observed.
For avertin-anesthetized mice, ECGs were recorded using 6 standard limb leads with a Silogic EC-60 monitor (Silogic Design Limited,13). For conscious mice, ECGs were recorded using AnonyMOUSE ECG Screening Tools (Mouse Specifics, Inc).14
A value of P≤0.05 was considered significant (2-tailed, unpaired Student’s t test or ANOVA test, StatView).
SR-BI/apoE double KO mice (dKO mice) fed a standard low fat/low cholesterol diet develop extensive aortic sinus atherosclerosis by 5 weeks of age and die prematurely.9 All of the dKO mice died between 5 to 8 weeks of age (50% mortality at 6 weeks; Figure 1A, solid line). No control mice died during this period (Figure 1A, dashed line). Before death, the dKO mice exhibited a 1- to 2-day period of progressively reduced activity and altered appearance (ruffled fur, abnormal gate, and occasionally labored breathing). We therefore explored the possibility that the dKO mice had cardiac abnormalities.
Extensive Myocardial Fibrosis
dKO hearts (Figures 1C and 1D) were enlarged relative to controls (eg, apoE KO, Figure 1B; see below) and exhibited pale, discolored patches (arrowheads, Figures 1C and 1D) not seen in any controls (eg, Figure 1B), suggesting extensive MI and scarring. These lesions were always present in the atrioventricular (AV) groove of the left ventricle (LV, Figure 1C) and frequently present at various locations on the right ventricular (RV) wall (Figure 1D), the LV wall, and/or the apex (not shown). Figure 2A shows a representative longitudinal section of a dKO heart (unperfused) stained with trichrome (healthy myocardium red, fibrotic tissue blue). Regions surrounding the mitral valves (not the valves themselves) and the LV outflow tract were invariably fibrotic (Figure 2A, B/C box and arrow). Higher magnification views (Figures 2B and 2C) show lesions contained fibrotic connective tissue (Figure 2B, arrow), few remaining myocytes (Figure 2C, arrow), and numerous large, dilated, apparently mononuclear inflammatory cells (Figures 2B and 2C, arrowheads), some of which were macrophages (brown, punctate F4/80 antibody staining, Figure 2G). Lesions in the RV free wall and more apical regions (Figure 2A, arrowheads, and Figures 2D and E) appeared more well-organized and contained fewer dilated cells than those in the outflow tract area and were characterized by extensive fibrosis, inflammation (Figure 2D), and in some cases, diffuse necrosis and myocardial scarring typical of healed infarcts (Figure 2E). Numerous macrophages were detected in these lesions and lesions in the papillary muscle (Figures 2G and 2J). Thus, macroscopic and microscopic observations revealed multiple MIs in the dKO mice.
In hypercholesterolemic animals, macrophages can accumulate extensive cytosolic lipid deposits (foam cells).4 Neutral lipid staining (oil red O, Figures 2H and 2K) of dKO hearts was particularly intense in macrophage-rich, fibrotic regions (Figures 2F through 2K) and appeared both in a concentrated, intense, globular pattern reminiscent of intracellular lipid (Figure 2H, arrow) and in a punctate pattern reminiscent of extracellular lipid (Figure 2H, black arrowheads).15 More diffusely distributed lipid was detected in non-fibrotic tissue throughout the heart between myocardial fibers (eg, Figure 2H, white-filled arrowheads). The codistribution of lipid and macrophages suggested the presence of macrophage foam cells. Future studies will determine if macrophage infiltration into fibrotic lesions is a consequence of and/or contributes to lesion development and if these lesions are similar to those in human inflammatory cardiomyopathies.
Intact hearts and LVs+septa (LV+S) and RVs from dKO mice were larger than those from age-matched controls (Figures 1B through 1D and Figure 3A, 1.6- to 1.8-fold greater mean heart-to-body weight ratios). Furthermore, dKO mice had a significantly lower body weight (15.3±2.0 g) than control animals (wild type: 20.7±4.3 g; SR-BI KO: 21.3±3.8 g; apoE KO: 18.8±2.3 g. P=0.002). This was confirmed by MRI analysis of LV+S tissue volume (Figure 3B). Increased tissue volume reflects a thicker LV+S wall (assuming no change in ventricular length). In contrast, the body weight–corrected LVEDVs were only slightly higher for dKO hearts (Figure 3B), suggesting only minor dilation. Thus, the increased size of dKO hearts was due primarily to increased ventricular tissue mass, possibly resulting from thickening of the wall near the outflow tract and compensatory thickening of the ventricular wall in response to reduced contractility (see following paragraph).
Hemodynamic analysis revealed that aortic systolic blood pressure and heart rate (HR) were significantly lower in dKO than in control mice (Table). dKO mice also had substantially lower LV systolic pressure (LVSP) and contractility (+dP/dt), indicating LV systolic dysfunction. A similar (3-fold) reduction in −dP/dt indicated impaired LV relaxation. The somewhat lower HR of dKO mice relative to controls (not observed in nonanesthetized mice) was not due to extracardiac neuronal influences (bilateral disruption of the vagal nerves did not eliminate the HR differences, not shown). Although reduced HR might have contributed to reduced blood pressure and contractility, and might complicate interpretation of differences in dP/dt values, it is unlikely that these relatively small baseline differences caused the large changes in both +dP/dt and −dP/dt. Furthermore, values for the products of pressures (P) with either +dP/dt or −dP/dt showed the same trends, indicating a minimal or insignificant influence of pressure on dP/dt values (not shown). The decreased aortic blood pressures and abnormal contractility and relaxation in these dKO mice are consistent with primary cardiac dysfunction. We also measured carotid arterial blood pressure in dKO mice (n=3) and control littermates (apoE KO mice with a heterozygous null mutation in SR-BI, n=3) at 3 (chloral hydrate anesthesia, 0.2 mg/g) and again at 4 (urethane anesthesia, 1 mg/g) weeks of age. We observed no blood pressure differences at 3 weeks and only a slight relative reduction in the dKO mice at 4 weeks (data not shown). Thus, it is unlikely that hypertension was responsible for the ventricular hypertrophy or other cardiac defects exhibited by dKO animals.
MRI images (Figure 4A) at end-diastole or end-systole show that, whereas the LVEDVs were similar (left panels, black arrows), the LV end systolic volumes (LVESVs) were substantially higher in dKO hearts than in the controls (right panels, black arrows). Consequently, the ejection fractions of the dKO hearts, a critical measure of heart function, were substantially lower (≈50%) than those of controls (Figure 4B).
In unanesthetized, conscious mice, normal ECG patterns were seen in controls (eg, apoE KO: Figure 4C, top; other controls not shown), whereas striking abnormalities were observed in 6 of 12 dKO mice. One exhibited an ST elevation of unclear etiology (not shown), and 5 showed severe ST depression (Figure 4C, bottom), indicating subendocardial ischemia.14,16⇓ In 5 of 8 dKO mice, but not in any controls, avertin anesthesia induced or uncovered cardiac conductance defects (Figure 4D, widened QRS, middle panel), which in some cases included escaped QRSs (middle panel) and progressed to complete AV blocks and bradycardic death (Figure 4D, bottom). These conductance defects were not observed in unanesthetized mice. Further studies will be required to determine if development of heart blocks might contribute to the spontaneous death of unanesthetized dKO mice. The gravimetric, hemodynamic, MRI, and ECG findings unequivocally demonstrate impaired heart function in dKO mice, possibly because of extensive myocardial fibrosis.
Coronary Artery Disease: Angiography and Histology
To determine if occlusive coronary artery disease may have contributed to cardiac dysfunction, we performed ex vivo angiography (Figure 5A). No obvious defects were apparent in control hearts (wild type, n=4, left panel; apoE KO, n=4, and SR-BI KO, n=3, data not shown). Five of seven dKO hearts examined showed stenoses and occlusions of branches of the left coronary arteries (eg, right panel, arrowheads), and there were 2 instances of apparent stenoses in the main coronary arteries (not shown).
Histological analyses of dKO hearts revealed extensive coronary artery disease (CAD) (Figures 5C through 5I). There were complex occlusions of major arterial branches in the LV free wall (9 of 10 mice analyzed), the septum (10 of 11), and the RV wall (11 of 12). No occlusions were seen in age-matched controls (apoE KO, Figure 5B; SR-BI KO and wild type not shown). Figure 5C shows a partially cellular, lipid-rich lesion almost completely occluding the lumen of a left coronary branching artery. Figure 5D shows fibrosis and inflammatory cells surrounding an occluded artery in the RV wall of another dKO mouse. Proximal lesions in coronary ostia (Figure 5E, arrow; adjacent to a typical, lipid-rich atheromatous plaque in the sinus, arrowhead) were also seen in 7 of 10 dKO mice. These complex lesions are probably responsible for the patchy MIs in the LV and RV. Figures 5F through 5I show serial cross-sections through an occluded coronary artery from another dKO mouse. Trichrome (Figure 5F) and lipid staining (Figure 5G) revealed numerous cholesterol clefts (arrows)15 within a lipid-rich, acellular, potentially ‘necrotic’ core.17,18⇓ Frequently, a substantial portion of the lesions appeared to be acellular, and some of these amorphous regions stained blue with trichrome (eg, Figure 5F), suggesting the presence of collagen. Immunostaining showed fibrin deposits in the core regions of 8 of 10 lesions observed in 3 of 3 dKO mice (eg, Figures 5H and 5I) but not in age-matched apoE KO controls (n=3, not shown). This thrombosis may be a consequence of bleeding into these complex lesions or perhaps plaque rupture.
The severe occlusive, fibrin-containing coronary arterial lesions, probable ischemia, multiple MIs, enlarged hearts, and cardiac dysfunction in very young (≈5 weeks old), low-fat/low-cholesterol fed SR-BI/apoE dKO mice provide a novel model of CHD. Both SR-BI and apoE normally play critical roles in lipoprotein metabolism and can protect mice from atherosclerosis.2–4,5,9,19–22⇓⇓⇓⇓⇓⇓⇓⇓ ApoE apparently influences atherosclerosis by mechanisms both independent of (or only subtly dependent on), as well as dependent on, its effects on plasma lipoprotein structure and abundance (reviewed in References 20 and 21). Hepatic expression of the HDL receptor SR-BI controls HDL structure and metabolism and plays an important role in reverse cholesterol transport (RCT), the transport via HDL of cholesterol from peripheral tissues (including atheromatous plaques) to the liver for recycling or biliary excretion.9,10,19,22–24⇓⇓⇓⇓⇓ SR-BI can also mediate cholesterol efflux from cells.25 SR-BI deficiency doubles plasma cholesterol levels and decreases biliary cholesterol secretion.9,10,24⇓⇓ Combined deficiencies of SR-BI and apoE profoundly alter lipoprotein metabolism,9 resulting in decreased biliary cholesterol and increased plasma choles-terol in VLDL-sized and in abnormally large HDL-like particles.9
The molecular mechanisms responsible for the dramatically accelerated occlusive atherosclerotic disease in the dKO mice relative to the apoE KO mice may include9 (1) changes in plasma proatherogenic and antiatherogenic lipoproteins, (2) altered cholesterol flux into or out of the artery wall, and (3) decreased RCT. SR-BI has also recently been shown to mediate HDL-dependent endothelial nitric oxide synthetase activation in vascular endothelium26 and the cellular uptake from lipoproteins of vitamin E,27–29⇓⇓ which can inhibit atherosclerosis in apoE KO mice.30–32⇓⇓ Loss of these activities may contribute to the accelerated atherosclerosis in dKO mice. Few of the current models of CHD exhibiting cardiac fibrosis, hypertrophy, heart dysfunction, and in some cases, premature death33–40⇓⇓⇓⇓⇓⇓⇓ involve primary defects in lipoprotein metabolism (see Introduction).5,6⇓ The SR-BI/apoE dKO mice are distinct because they have extensive coronary artery lesions with fibrin deposition and spontaneously develop extensive MIs on a standard chow diet at a very young age (5 weeks). Severe cardiac dysfunction and repetitive MIs (with associated risk of arrhythmias) due to occlusive CAD are likely to contribute to their premature deaths. The possible roles of associated myocardial inflammation and lipid accumulation in the myocardium, and of other metabolic/organ systems in the premature death of the dKO mice, remain to be determined (eg, we have observed a reduced hematocrit and reticulocytosis in dKO mice41 that might have resulted in increased susceptibility to myocardial ischemia). Nevertheless, the sudden bradycardic death that occasionally accompanied avertin anesthesia (Figure 4D) was almost certainly a consequence of the induction of cardiac conductance defects and complete AV block.
The occlusive lesions in coronary arteries of SR-BI/apoE dKO mice were highly complex, containing cholesterol clefts and fibrin deposits. Although there are previous reports of spontaneous atherosclerotic lesions in older apoE KO mice that stain positively with anti-fibrinogen antibodies and/or show evidence of necrotic zones, abundant cholesterol clefts, and hemorrhage,17,42–46⇓⇓⇓⇓⇓ we are not aware of other reports of direct immunohistochemical detection of fibrin in murine atherosclerotic plaque. Additional studies are required to determine the mechanism of fibrin deposition (eg, hemorrhage due to plaque fission or rupture,47 erosion of small vessels supplying the plaques,48 or some other mechanism). In the dKO mice, fibrin deposition in plaque might either contribute to or be a consequence of occlusive lesion growth, or both. Although not required for atherosclerotic plaque formation in apoE KO mice,44 fibrin deposition in the context of repetitive vascular injury might stimulate the growth of plaques.43
The occlusive lesions in SR-BI/apoE dKO mice apparently result in ischemia (see Figure 4C) and the formation of multiple patchy MIs with variable sizes and locations. Future studies will be required to determine if thrombosis plays a role in this pathology. In humans, multiple infarcts lead to a gradual decline in systolic function, first manifest under stress and later seen under resting conditions. It is striking that the young dKO mice (5 to 6 weeks old) at rest exhibit systolic dysfunction (hemodynamic and EF abnormalities). This and an abnormally high heart-to-body weight ratio49 indicate severe cardiac dysfunction. Furthermore, in humans with heart disease50,51⇓ and SR-BI/apoE dKO mice, anesthesia can induce substantial conductance abnormalities (eg, brady-arrhythmias and AV blocks). Thus, these dKO mice may prove to be a useful model to investigate the mechanisms underlying the development of complex CAD and MI. They may also be useful for preclinical testing of potential genetic and/or pharmacological therapies for CHD.
This work was supported by grants HL41484, HL64737, HL66105, and HL52212 to M.K., and HL63609 and HL53793 to M. Simons and M.J.P. from the US National Institutes of Health and grant EIG 9940074 from the American Heart Association to M. Simons. A.B. was a Human Frontiers Science Program postdoctoral fellow. B.L.T. was a Medical Research Council of Canada postdoctoral fellow. We thank J. Bao, A. Bashir, D. Burstein, J. Chen, P. Christie, E. Edelman, C. Egles, T. Hampton, R. Hynes, M. Josephson, H. Kanji, J. M. Kwiecien, F. Mamuya, H. Miettinen, J. Munasinghe, R. Oppenheimer, M. Penman, F. Schoen, R. Thiro Wirasinghe, and M. Viñals for technical assistance, advice, and/or helpful discussions.
Original received July 10, 2001; revision received December 19, 2001; accepted December 19, 2001.
- ↵Zhang SH, Reddick RL, Piedrahita JA, Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science. 1992; 258: 468–471.
- ↵Nakashima Y, Plump AS, Raines EW, Breslow JL, Ross R, ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb. 1994; 14: 133–140.
- ↵Caligiuri G, Levy B, Pernow J, Thoren P, Hansson GK. Myocardial infarction mediated by endothelin receptor signaling in hypercholesterolemic mice. Proc Natl Acad Sci U S A. 1999; 96: 6920–6924.
- ↵Herrera VL, Makrides SC, Xie HX, Adari H, Krauss RM, Ryan US, Ruiz-Opazo N. Spontaneous combined hyperlipidemia, coronary heart disease and decreased survival in Dahl salt-sensitive hypertensive rats transgenic for human cholesteryl ester transfer protein. Nat Med. 1999; 5: 1383–1389.
- ↵Trigatti B, Rayburn H, Vinals M, Braun A, Miettinen H, Penman M, Hertz M, Schrenzel M, Amigo L, Rigotti A, Krieger M. Influence of the high density lipoprotein receptor SR-BI on reproductive and cardiovascular pathophysiology. Proc Natl Acad Sci U S A. 1999; 96: 9322–9327.
- ↵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.
- ↵Stary HC. The Evolution of Human Atherosclerotic Lesions. West Point, Pa: Merck & Co, Inc; 1993.
- ↵Rosenfeld ME, Polinsky P, Virmani R, Kauser K, Rubanyi G, Schwartz SM. Advanced atherosclerotic lesions in the innominate artery of the ApoE knockout mouse. Arterioscler Thromb Vasc Biol. 2000; 20: 2587–2592.
- ↵Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM, Vargas SO, Sampson BA, Schoen FJ. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2000; 20: 1262–1275.
- ↵Mardones P, Quinones V, Amigo L, Moreno M, Miquel JF, Schwarz M, Miettinen HE, Trigatti B, Krieger M, VanPatten S, Cohen DE, Rigotti A. Hepatic cholesterol and bile acid metabolism and intestinal cholesterol absorption in scavenger receptor class B type I-deficient mice. J Lipid Res. 2001; 42: 170–180.
- ↵Ji Y, Jian B, Wang N, Sun Y, Moya ML, Phillips MC, Rothblat GH, Swaney JB, Tall AR. Scavenger receptor BI promotes high density lipoprotein-mediated cellular cholesterol efflux. J Biol Chem. 1997; 272: 20982–20985.
- ↵Mardones P, Strobel P, Miranda S, Leighton F, Quiñones V, Amigo L, Rozowski J, Krieger M, Rigotti A. Role of the scavenger receptor class B type I (SR-BI) in α-tocopherol metabolism in mice. J Nutr. In press.
- ↵Witt W, Kolleck I, Fechner H, Sinha P, Rustow B. Regulation by vitamin E of the scavenger receptor BI in rat liver and HepG2 cells. J Lipid Res. 2000; 41: 2009–2016.
- ↵Terasawa Y, Ladha Z, Leonard SW, Morrow JD, Newland D, Sanan D, Packer L, Traber MG, Farese RV. Increased atherosclerosis in hyperlipidemic mice deficient in alpha -tocopherol transfer protein and vitamin E. Proc Natl Acad Sci U S A. 2000; 97: 13830–13834.
- ↵Thomas SR, Leichtweis SB, Pettersson K, Croft KD, Mori TA, Brown AJ, Stocker R. Dietary cosupplementation with vitamin E and coenzyme q(10) inhibits atherosclerosis in apolipoprotein E gene knockout mice. Arterioscler Thromb Vasc Biol. 2001; 21: 585–593.
- ↵Hasenfuss G. Animal models of human cardiovascular disease, heart failure and hypertrophy. Cardiovasc Res. 1998; 39: 60–76.
- ↵Bachmaier K, Mair J, Offner F, Pummerer C, Neu N. Serum cardiac troponin T and creatine kinase-MB elevations in murine autoimmune myocarditis. Circulation. 1995; 92: 1927–1932.
- ↵Penninger JM, Bachmaier K. Review of microbial infections and the immune response to cardiac antigens. J Infect Dis. 2000; 181 (suppl 3): S498–S504.
- ↵Holm TM, Braun A, Trigatti BL, Brugnara C, Sakamoto M, Krieger M, Andrews NC. Failure of red blood cell maturation in mice with defects in the HDL receptor SR-BI. Blood. In press.
- ↵Sjoland H, Eitzman DT, Gordon D, Westrick R, Nabel EG, Ginsburg D. Atherosclerosis progression in LDL receptor-deficient and apolipoprotein E-deficient mice is independent of genetic alterations in plasminogen activator inhibitor-1. Arterioscler Thromb Vasc Biol. 2000; 20: 846–852.
- ↵Eitzman DT, Westrick RJ, Xu Z, Tyson J, Ginsburg D. Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery. Blood. 2000; 96: 4212–4215.
- ↵Seo HS, Lombardi DM, Polinsky P, Powell-Braxton L, Bunting S, Schwartz SM, Rosenfeld ME. Peripheral vascular stenosis in apolipoprotein E-deficient mice: potential roles of lipid deposition, medial atrophy, and adventitial inflammation. Arterioscler Thromb Vasc Biol. 1997; 17: 3593–3601.
- ↵Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V, Fallon JT. Macrophage infiltration in acute coronary syndromes: implications for plaque rupture. Circulation. 1994; 90: 775–778.
- ↵Oliver PM, Fox JE, Kim R, Rockman HA, Kim HS, Reddick RL, Pandey KN, Milgram SL, Smithies O, Maeda N. Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A. Proc Natl Acad Sci U S A. 1997; 94: 14730–14735.