Published online before print February 3, 2005, doi: 10.1161/01.ATV.0000158310.64498.ac
© 2005 American Heart Association, Inc.
Atherosclerosis & Lipoproteins |
Lymphocytes Are Not Required for the Rapid Onset of Coronary Heart Disease in Scavenger Receptor Class B Type I/Apolipoprotein E Double Knockout Mice
From the Department of Biology (S.L.K., M.K.), Massachusetts Institute of Technology, Cambridge; and Division of Cardiology Department of Medicine (M.H.P.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass.
Correspondence to Monty Krieger, Room 68-483, Biology Department, Massachusetts Institute of Technology, Cambridge, MA 02139. E-mail krieger{at}mit.edu
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Abstract |
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Objective— Scavenger receptor class B type I (SR-BI)/apolipoprotein E (apoE) double knockout (dKO) mice exhibit many features of human coronary heart disease (CHD), including occlusive coronary atherosclerosis, cardiac hypertrophy, myocardial infarctions, and premature death. Here we determined the influence of B and T lymphocytes, which can contribute to atherosclerosis, ischemia–reperfusion injury, and cardiomyocyte death, on pathology in dKO mice.
Method and Results— The lymphocyte-deficient SR-BI/apoE/recombination activating gene 2 (RAG2) triple knockout mice and corresponding dKO controls generated for this study exhibited essentially identical lipid-rich coronary occlusions, myocardial infarctions, cardiac dysfunction, and premature death (average lifespans 41.6±0.6 and 42.0±0.5 days, respectively).
Conclusions— B and T lymphocytes and associated immunoglobulin-mediated inflammation are not essential for the development and progression of CHD in dKO mice. Strikingly, the dKO mice bred for this study (mixed C57BL/6xSV129xBALB/c background; strain 2) compared with the previously described dKO mice (75:25 C57BL/6:SV129 background; strain 1) had a shorter mean lifespan and steeper survival curve, characteristics especially attractive for studying the effects of environmental, pharmacological, and genetic manipulations on cardiac pathophysiology.
SR-BI/apoE double knockout mice exhibit occlusive atherosclerotic coronary heart disease (CHD) characterized by myocardial infarctions, cardiac dysfunction, and premature death. Analysis of B-cell– and T-cell–deficient SR-BI/apoE/RAG2 triple knockout mice established that B and T lymphocytes do not play a key role in the pathophysiology of this model of human disease.
Key Words: atherosclerosis • HDL receptor • myocardial infarction • RAG2 • echocardiography
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Introduction |
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Murine models of dyslipidemia, such as the apolipoprotein E (apoE) or low-density lipoprotein (LDL) receptor knockout (KO) mice, have been used extensively to study atherosclerosis. However, even when subjected to high-fat/high-cholesterol diets, all but one of these hypercholesterolemia and atherosclerosis systems usually do not result in spontaneous development of occlusive coronary artery disease, myocardial infarction (MI), cardiac dysfunction, or the premature death that are hallmarks of human coronary heart disease (CHD). The exception, mice doubly deficient for the HDL receptor scavenger receptor class B type I (SR-BI) and apoE (double KO [dKO]) not only exhibit extensive aortic sinus and occlusive coronary arterial atherosclerosis (advanced plaques with fibrous caps, fibrin deposition, and cholesterol clefts), but they also experience severe CHD at a very young age (4 to 6 weeks).1–3 The hearts of dKO mice are hypertrophic and exhibit left ventricular (LV) dilation and multiple, large MIs. Severe cardiac dysfunction is demonstrated by multiple ECG abnormalities (ST segment elevation and depression, anesthesia-induced conductance abnormalities [eg, bradyarrhythmias, atrioventricular blocks]), a 70% reduction in ±dP/dT, and 50% reduced ejection fraction. The mice die between 5 and 8 weeks of age (mean 6 weeks). Thus, the many similarities in CHD of dKO mice and humans raised the possibility that these mice may help in the study of the pathophysiology of CHD and genetic, pharmacological, and environmental approaches for its prevention and treatment.
B and T lymphocytes can modulate development of atherosclerotic lesions and damage to cardiac tissue,4–10 and thus may contribute to pathophysiology in dKO mice. Disruption of the recombination activating genes (RAG1 or RAG2)11,12 renders mice B and T cell–deficient and reduces the rate of atherosclerosis development in low-fat chow-fed apoE KO mice. Thus, lymphocytes contribute to but are not essential for murine atherogenesis. The influence of lymphocytes on lesion development in apoE KO mice is dramatically reduced when atherosclerosis is accelerated by a high-fat/high-cholesterol diet that exacerbates hypercholesterolemia.9,13,14 In addition to participating in atherosclerosis in occlusive CHD, lymphocytes may directly contribute to ischemia–reperfusion injury, myocardial damage, and cardiomyocyte death.15–19 For example, anticardiac antibodies and sensitized T lymphocytes have been detected in patients with acute MI.20 Lymphocytes have also been implicated in cardiomyocyte injury during autoimmune myocarditis,21–25 and spontaneous RAG2-dependent, lymphocyte-mediated immune responses in mice lacking the negative immunoregulatory receptor PD-1 cause dilated cardiomyopathy and death from congestive heart failure.26
Here we established the presence of T cells in the hearts of dKO mice. We explored the roles of lymphocytes in murine CHD1,3 by generating and analyzing B and T cell–deficient SR-BI/apoE/RAG2 triple KO (tKO) and corresponding dKO control mice. Complete deficiency of B and T lymphocytes had no discernable effects on CHD and premature death. Thus, lymphocytes and associated antibody-driven inflammation are not essential for cardiac pathology in dKO mice.
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Materials and Methods |
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SR-BI(–/–)/apoE(–/–)/RAG2(–/–) tKO mice and control SR-BI(–/–)/apoE(–/–)/RAG2(+/+) dKO (strain 2) mice were generated by crossing SR-BI(+/–) apoE(–/–) females (75:25 C57BL/6:SV129 background; strain 1)1 with SR-BI(–/–)/RAG2(–/–) males (mixed C57BL/6xSV129xBALB/c background).27 The offspring SR-BI(+/–)/apoE(+/–)/RAG2(+/–) females were then crossed to sibling SR-BI(–/–)/apoE(+/–)/RAG2(+/–) males to generate littermate isolates of tKO and dKO (strain 2) mice as well as breeder mice that were used to maintain the colonies and generate subsequent experimental animals. dKO (strain 2) animals differed somewhat (see below) from the previously described "strain 1" dKO (75:25 C57BL/6:SV129 background)1 mice. Unless otherwise noted, all dKOs used were from strain 2. For descriptions of all other materials and methods, demonstration of B and T cell deficiencies of the tKO mice, analysis of hematocrits, and a description of lymphoid tissues, please see the online data supplement (available online at http://atvb.ahajournals.org).
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Results |
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At 5 to 6 weeks of age, the hearts of dKO mice exhibit extensive fibrosis around the ventricular outflow tract and patchy MIs in the apex, right ventricular wall, and interventricular septum.3 Figure 1A shows a representative trichrome-stained longitudinal section (41-day-old female). Healthy myocardium is stained red and fibrotic tissue blue. Although hematoxylin and eosin staining suggested extensive inflammatory infiltration,3 the role of B or T lymphocytes in this CHD had not been directly examined.
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Immunohistochemical Analysis of Lymphocytes in dKO Hearts
The pan B-cell marker anti-CD19 did not stain heart sections (data not shown), indicating these cells were absent but not eliminating a potential role for immunoglobulin-mediated autoimmune inflammatory heart disease.28,29 However, clusters of cells that tended to coincide with regions of immune-infiltrated and damaged tissue stained with antibodies against the T-cell marker CD4 (Figure 1B and C) but not with isotype control antibodies (data not shown), raising the possibility that T lymphocytes might contribute to myocardial injury. Others have suggested that quantitation of lymphocyte infiltration can be confounded by the antibody and immunohistochemical technique used;30 therefore, no attempt was made to count positively staining cells and correlate them with the extent of tissue damage.
To definitively determine whether lymphocytes play a role in cardiac pathophysiology, we generated and characterized a line of SR-BI(–/–)/apoE(–/–)/RAG2(–/–) tKO mice with total lymphocyte deficiency (see supplemental material).12 The absence of B- lymphocyte function in tKOs was confirmed by analysis of plasma levels of IgG in dKO and tKO mice. dKO mice had plasma total IgG titers similar to those of SR-BI+/+ApoE–/–Rag2+/+ control mice (0.51±0.12 versus 0.60±0.089 mg/mL; P=0.608). Plasma total IgG titers for tKO mice and SR-BI+/+ApoE–/–Rag2–/– control mice fell below the range of detection of the assay kit used, even at sample concentrations that were 5 and 50x higher than that used for the plasma of Rag2+/+ control mice, establishing the absence of detectable IgG in tKO mice as expected.
Plasma Lipids and Lipoprotein Profiles
Disruption of the RAG2 (or RAG1) gene has been shown to lower plasma cholesterol levels in apoE(–/–) or LDL receptor(–/–) mice.9,31,32 Thus, we compared the plasma lipid levels in dKO and tKO mice because dyslipidemia (hypercholesterolemia, abnormally high unesterified cholesterol [UC] to total cholesterol [TC] ratio) is thought to be responsible for occlusive atherosclerosis and CHD in dKO mice.2,3 Consistent with previous reports,9,32 there was a small but significant reduction in plasma UC and phospholipids in tKO animals compared with dKOs (UC [mg/dL] 655±30 versus 767±40, respectively, P=0.03; and phospholipids [mg/dL] 586±28 versus 681±34, respectively, P=0.04) but no statistically significant differences in plasma TCs (909±38 versus 1001±54 mg/dL, respectively; P=0.17) or UC/TC ratios. Fast protein liquid chromatography (FPLC) analysis of plasma lipoproteins (Figure 2) revealed no major differences in the lipoprotein TC profiles (n=4 for each group). The slightly higher amounts of cholesterol in the very-low-density lipoprotein (VLDL)–size fractions from the dKO mice relative to tKO mice is similar to that reported by Reardon et al for apoE KO mice.32 The minimal alterations in plasma lipoproteins by RAG2 gene disruption appear unlikely to differentially influence atherosclerosis and CHD in dKO and tKO mice.
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Cardiac Histopathology
Trichrome staining of 
6-week-old tKO hearts demonstrated extensive myocardial fibrosis similar to that in dKO mice (Figure 1D; compare with 1A). As in dKO mice,3 neutral lipid deposits (oil red O staining) and macrophage foam cell formation (F4/80 immunohistochemical staining) coincided with regions of fibrosis (data not shown). The absence of CD4+ cells in the hearts of tKO mice (Figure 1E and 1F) confirmed their B and T cell deficiencies (RAG2(–/–) phenotypes). Thus, neither B nor T cells were required for extensive fibrosis/infarction.
Figure 3 shows that lipid-rich occlusive atherosclerotic lesions in coronary arteries of tKO mice were similar to those in dKO mice. There were no significant differences in the numbers of nonoccluded, partially occluded (<50% occluded) and completely occluded (>50% occluded) coronary arteries (n=4 for each group). Severely occluded arteries were prevalent in areas with myocardial fibrosis, especially near the upper ventricular outflow regions. Some occlusions contained significant cellular components; others were predominantly acellular. Thus, lymphocytes did not markedly influence the nature of the occlusive coronary disease and cardiac damage.
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Cardiac Structure and Function
Echocardiography was used to assess cardiac function and hypertrophy33–37 in lightly anesthetized (pentobarbital; 25 mg/kg IP) dKO and tKO mice and their SR-BI–positive littermate controls (Table). No significant differences between RAG2(–/–) and RAG2(+/+) control mice were observed; therefore, all controls were pooled.
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The values of posterior wall thickness (PWT) and LV mass (absolute and normalized to body weight) for the dKO and tKO mice were not significantly different from each other but were greater than those of controls. The quantitative effects of CHD on the PWT seen here are similar to those in other forms of cardiac dysfunction.34 The echocardiographically determined increases in heart size in the dKO and tKO mice were confirmed by gravimetric analysis (Table). The heart-to-body weight ratios of the dKO and tKO mice were similar (P=0.2405) and 1.9- and 1.8-fold larger than for age-matched controls (P<0.0001). The body weights for the dKO and tKO mice were similar (16.8±0.8 g [n=19] and 16.4±0.4 g [n=17], respectively) and smaller than that of their littermate controls (18.3±0.6 g [n=13]). The smaller size of SR-BI(–/–)/apoE(–/–) mice compared with SR-BI–positive controls was reported previously.3
LV fractional shortening (FS; [LV end-diastolic diameter–LV end-systolic diameter/LV end-diastolic dimension]) was used as a measure of the systolic function of the heart. Figure 4 shows representative M-mode and 2D echocardiographic images of control, dKO, and tKO mice. The mean FS for control mice was 50.1%±5.0%, corresponding to data reported by several groups for conscious38 and anesthetized33,35,37 mice. There were clear defects in LV wall motion in dKO and tKO mice compared with controls (Table; Figure 4). dKOs and tKOs had 50% lower FS than control mice, demonstrating a substantial deficit in cardiac contractility. Importantly, there was no significant difference in FS between the dKO and tKO mice (26.1%±6.2% versus 24.3%±4.0%; P=0.7960). Reported FS values of 10% to 30% for surgically induced models of MI and congestive heart failure,33,35 as well as genetically induced dilated cardiomyopathy,26 correspond well to the low values seen in the dKO and tKO mice.
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During echocardiography, dKO and tKO mice exhibited significantly lower heart rates than those of control mice, although they did not differ from each other (395±19 versus 386±24 bpm, respectively). Numerous studies suggest that anesthesia administered before echocardiography can depress heart rate38–40 that can, in turn, influence echocardiographically determined parameters of cardiac function, including contractility and FS.39,40 Moreover, these effects vary with type and dosage of anesthetic and mouse strain studied.38–40 However, some studies of mice undergoing conscious echocardiography demonstrate perturbations in heart rate, including bradycardia before training and tachycardia after training.38,39 The mean heart rate for our control mice anesthetized with a low dose of pentobarbital (522±24 bpm) was similar to that measured for conscious mice during echocardiography as reported by Takuma et al40 and unrestrained mice undergoing telemetry,39 suggesting the low dose of anesthetic used did not depress heart rate in the control mice. However, electrocardiography of dKOs has shown these mice to be hypersensitive to certain anesthetic agents.3 Their rapid deterioration in health and short lifespans prevent dKO mice from enduring the stress of multiple training sessions required for conscious, unanesthetized echocardiography. Previous electrocardiographic studies have shown that conscious unanesthetized dKO mice exhibit reduced heart rates as they approach the terminal stage of disease30(data not shown). (Most [12 of 16] of the dKO and tKO mice exhibited electrocardiographic abnormalities during echocardiographic analysis [ECG tracings in left panels of Figure 4 and data not shown.]) Therefore, even if echocardiographic data were obtained without anesthesia, it is likely that the dKOs and tKOs would still have exhibited heart rates significantly lower than control mice. Given these complications, it is not possible to distinguish with certainty the effects of anesthesia from those of advanced disease on heart rate and echocardiographic data obtained from dKOs and tKOs, although it seems likely that the abnormalities observed were attributable, at least in part, to the underlying pathology and not solely consequences of enhanced sensitivity of these mice to anesthetics.
Effects of Immunodeficiency on Survival
We next determined whether inactivation of the RAG2 gene altered the life expectancies of these mice. Figure 5 shows that the survival curves for dKO (strain 2; black) and tKO (red) mice were virtually identical (mean survival times 42.0±0.5 days (n=65) and 41.6±0.6 days (n=35), respectively [P=0.3594; log rank test]). RAG2-deficient mice have been reported to exhibit a normal lifespan when maintained in a pathogen-free facility such as that used here.41 Thus, although it is possible that absence of an influence of RAG2 deficiency on survival of dKO mice could have arisen because of compensatory effects on the kinetics of the fatal pathologies normally exhibited by dKO mice and on independent processes attributable to the immunodeficiency, this seems unlikely. Therefore, B and T cells do not significantly contribute to the fatal pathophysiology in dKO mice.
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The survival curve of the dKO mice bred for this study (strain 2; black) significantly differed from that of the previously described SR-BI(–/–)/apoE(–/–) dKO mice (strain 1; blue),1,3 revealing that genetic background variation can significantly impact lifespan. The mean survival of strain 1 (45.9±0.9 days; n=61) was significantly longer than that of strain 2 (P=0.0001). Remarkably, 82% of strain 2 dKOs died within an exceptionally narrow 9-day window (38 to 47 days of age), whereas the comparable range in strain 1 mice was 16 days (40 to 56 days). These differences are presumably attributable to their different genetic backgrounds (see Materials and Methods).
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Discussion |
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Low-fat chow–fed SR-BI/apoE dKO mice rapidly develop fatal occlusive atherosclerotic CHD that closely resembles that in humans.1–3 The simultaneous absence of apoE and the HDL receptor SR-BI, both of which have been shown to protect against murine atherosclerosis,42,43 is responsible for hypercholesterolemic dyslipidemia exceeding that observed in either single KO mouse. Advanced atherosclerotic plaques can be seen in the hearts of these mice as early as 4 to 4.5 weeks of age1,3and appear to be critically important for CHD pathogenesis.1–3
Here we examined the role of lymphocytes in the CHD of dKO mice by generating immunodeficient tKO mice, which are dKO mice lacking B and T cells because of homozygous disruption of the RAG2 recombinase gene.12 We compared the phenotypes of dKO and tKO mice because previous studies have implicated lymphocytes in atherosclerosis and myocardial damage after ischemic injury (see Introduction). Although occlusive coronary atherosclerosis in dKO mice appears to be the primary cause of CHD and premature death in dKO animals,3 other mechanisms could contribute to pathology. For example, immunoglobulin-mediated inflammatory heart disease can cause murine MI and death, even in the absence of hypercholesterolemia.28,29,44 Thus, analysis of the B and T cell–deficient tKO mice permitted us to determine whether immunoglobulin-mediated or other B and T cell–associated inflammatory heart disease played a role in this CHD model.
We observed that although the immune infiltrate in the damaged myocardium of dKO mice contains T cells, there were apparently no differences in the occlusive coronary atherosclerosis, MI, cardiac dysfunction, and survival of dKO and tKO mice. Thus, immunoglobulin-mediated inflammatory heart disease is not a critical underlying mechanism in CHD in dKO mice, and B and T cells do not play a key role in the onset or progression of disease in this model. These findings are consistent with the previous observations that B and T cells can influence, but are not essential for, murine atherosclerosis and that their influence on atherogenesis is difficult to detect in apoE KO mice with high-fat diet–induced, exceptionally high hypercholesterolemia.9,14 In dKO and high-fat fed apoE KO mice, the extreme hypercholesterolemia appears to eclipse the influence of B- and T-cell deficiency on pathology. Additional studies are necessary to determine the influence on CHD in dKO mice of other immune cells, including macrophages, neutrophils, and natural killer cells, which are present in RAG2-deficient mice.45–47
Interestingly, the strain of dKO mice generated for this study by extensive inbreeding (strain 2) generated animals that exhibited a significantly shorter period over which the most (82%) mice died (38 to 47 days) than that of the mice used for the first report of this model3(40 to 56 days; strain 1). Thus, these new strains of dKO and tKO mice appear to be especially attractive for evaluating the consequences of environmental, pharmacological, and genetic manipulations on the pathophysiology in this CHD model. Disease progression is rapid, variation in times of death is low (relatively few animals needed to see statistically significant alterations in disease progression), and attempts to alter disease progression in the tKO mice by treatment with biological agents (eg, antibodies and viral vectors) cannot illicit lymphocyte-mediated immune responses that might otherwise confound analysis of the results from immunocompetent animals. Furthermore, additional analysis of the strain 1 and strain 2 mice may possibly help identify modifier genes that influence the rates of disease progression and premature death in these animals.
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Acknowledgments |
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This work was supported by National Institutes of Health grants HL66105 and HL64737 (to M.K.). We thank E. Binello, J. Allen, S. Sullivan, C. McPherson, C. Dillon, S. Zhang, A. Yesilaltay, K. Makikallio, K. Runge, Y. Zhu, and S. Vassallo for assistance.
Received August 10, 2004; accepted January 18, 2005.
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