Lymphocytes Are Not Required for the Rapid Onset of Coronary Heart Disease in Scavenger Receptor Class B Type I/Apolipoprotein E Double Knockout Mice

Karackattu, Sharon L.; Picard, Michael H.; Krieger, Monty

doi:10.1161/01.atv.0000158310.64498.ac

Cited by 20 publications

(18 citation statements)

References 52 publications

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“…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onset occlusive coronary arterial atherosclerosis, (to date, occlusive thrombi have not been observed in these mice [unpublished data, 2005]), associated MI does not usually accompany the aortic atherosclerosis seen in other common murine models of hyperlipidemia, 24,47-51 the dKO mouse,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.…”

Section: Discussionsupporting

confidence: 87%

“…To investigate mechanisms underlying the extended lifespan of the tKOs, we further characterized the mice at Ϸ6 weeks (37 to 48 days) of age, designated dKO-6 and tKO-6 and Ϸ 9 weeks (60 to 68 days, tKO-9). As previously reported, by 6 weeks of age Ϸ50% of the dKO mice died and the surviving animals exhibited occlusive atherosclerosis, MI, and heart dysfunction, 3,4,21 whereas virtually all of the tKO mice were alive. We expected that surviving tKO-9 mice (mean age of death) might resemble dKO-6 mice.…”

supporting

confidence: 76%

“…Previous studies, in which B-and T-lymphocyte production was blocked by deficiency in the RAG2 gene, demonstrated that B-and T-lymphocyte-mediated inflammatory heart disease is not essential for CHD in dKO mice. 21 In an attempt to directly test the role of atherosclerosis in this CHD, we generated SR-BI/apoE/HL tKO mice with the goal of changing the rate of onset or progression of atherosclerosis. Numerous reports indicate that HL can have either pro-atherogenic or anti-atherogenic activities in humans and mice, depending on the details of the system undergoing study.…”

Section: Discussionmentioning

confidence: 99%

“…In dKO-6 mice ( Figure 4D and 4K), severe and partially occluded lesions were common (36Ϯ4%, 28Ϯ3%, respectively, nϭ5 mice), whereas 36Ϯ3% of the vessels were open. Occlusions, which were either predominantly acellular or contained significant cellular components, 3,21 were prevalent in areas with myocardial fibrosis, especially near the upper ventricular outflow regions. Unlike the dKO-6s, most vessels in tKOs-6s ( Figure 4E and 4K, nϭ5) were completely open (62Ϯ9%), with 31Ϯ8% partially and only 6Ϯ3% severely occluded.…”

Section: Effects Of Hepatic Lipase Deficiency On Aortic Root and Occlmentioning

confidence: 99%

“…The offspring SR-BI(ϩ/Ϫ)/apoE(ϩ/Ϫ)/HL(ϩ/Ϫ) females were then crossed to sibling SR-BI(Ϫ/Ϫ)/apoE(ϩ/Ϫ)/HL(ϩ/Ϫ) males to generate littermate tKO and dKO mice as well as breeder mice that were used to maintain the colonies. Animals were fed standard chow (Prolab 3000; PMI Feeds, St. Louis, Mo) and housed as previously described 21 and experiments followed MIT Animal Care guidelines. No significant differences were observed between males and females.…”

mentioning

confidence: 99%

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

Karackattu

Trigatti

Krieger

2006

ATVB

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Objective-SR-BI/apolipoprotein (apo) E 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 effects on this pathology of hepatic lipase (HL) deficiency, which has been shown to significantly modulate atherosclerosis. Method and Results-The SR-BI/apoE/HL triple knockout (tKO) mice generated for this study lived significantly longer (37%) than corresponding dKO controls (average lifespans: 63.0Ϯ0.8 versus 46.0Ϯ0.3 days), despite their increased plasma cholesterol levels. At 6 weeks of age, compared with dKO mice, tKOs exhibited significantly less aortic root and coronary artery occlusive atherosclerosis, and improved cardiac structure and function. However, by 9 weeks of age the hearts of tKO mice exhibited lipid-rich coronary occlusions, myocardial infarctions, and cardiac dysfunction essentially identical to that of 6-week-old dKO mice. Conclusions-HL-deficiency delays the onset and/or progression of atherosclerosis via a SR-BI-independent mechanism.Extent of occlusive coronary arterial lesions was more closely associated with cardiac dysfunction and lifespan than the amount of aortic root atherosclerosis, suggesting that these occlusions in dKO mice are responsible for ischemia, myocardial infarctions, and premature death. Key Words: atherosclerosis Ⅲ hepatic lipase Ⅲ high density lipoprotein receptor Ⅲ myocardial infarction T hough apolipoprotein E (apoE) or low-density lipoprotein receptor (LDLR) knockout (KO) murine models of dyslipidemia are often used to study lipoprotein metabolism and atherosclerosis, 1 they usually do not exhibit spontaneous occlusive coronary artery disease, myocardial infarction (MI), cardiac dysfunction and premature death, hallmarks of human coronary heart disease (CHD). Double knockout (dKO) mice deficient in the high-density lipoprotein (HDL) receptor (scavenger receptor class B type I, SR-BI) and apoE exhibit extensive aortic sinus atherosclerosis (advanced plaques with fibrous caps 2 that contain macrophages [unpublished data, 2005]), occlusive coronary arterial atherosclerosis (cellular and acellular plaques containing lipid [including cholesterol clefts], collagen, and fibrin deposits 3 ), and acute CHD when young (4 to 6 weeks old). 2-4 At 6 weeks of age, dKO hearts exhibit multiple, large infarctions with extensive fibrosis around the ventricular outflow tract and patchy MIs in the apex, right ventricular wall and interventricular septum. 3 In addition, they are hypertrophic with LV dilation, and exhibit severe dysfunction, including multiple electrocardiographic (ECG) abnormalities (ST elevation and depression, anesthesia induced conductance abnormalities (eg, bradyarrhythmias, AV blocks)), a 70% reduction in ϮdP/dT, and 50% reduced ejection fraction. The dKO mice die between 5 and 8 weeks of age (mean 6 weeks). 2,3 Similarities between dKO and human CHD raised the possibility that these mice may help to ...

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Section: Discussionsupporting

confidence: 87%

supporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Effects Of Hepatic Lipase Deficiency On Aortic Root and Occlmentioning

confidence: 99%

mentioning

confidence: 99%

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

Karackattu

Trigatti

Krieger

2006

ATVB

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HDL Biogenesis, Remodeling, and Catabolism

Zannis

Fotakis

Κούκος

et al. 2014

Handbook of Experimental Pharmacology

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In this chapter, we review how HDL is generated, remodeled, and catabolized in plasma. We describe key features of the proteins that participate in these processes, emphasizing how mutations in apolipoprotein A-I (apoA-I) and the other proteins affect HDL metabolism. The biogenesis of HDL initially requires functional interaction of apoA-I with the ATP-binding cassette transporter A1 (ABCA1) and subsequently interactions of the lipidated apoA-I forms with lecithin/cholesterol acyltransferase (LCAT). Mutations in these proteins either prevent or impair the formation and possibly the functionality of HDL. Remodeling and catabolism of HDL is the result of interactions of HDL with cell receptors and other membrane and plasma proteins including hepatic lipase (HL), endothelial lipase (EL), phospholipid transfer protein (PLTP), cholesteryl ester transfer protein (CETP), apolipoprotein M (apoM), scavenger receptor class B type I (SR-BI), ATP-binding cassette transporter G1 (ABCG1), the F1 subunit of ATPase (Ecto F1-ATPase), and the cubulin/megalin receptor. Similarly to apoA-I, apolipoprotein E and apolipoprotein A-IV were shown to form discrete HDL particles containing these apolipoproteins which may have important but still unexplored functions. Furthermore, several plasma proteins were found associated with HDL and may modulate its biological functions. The effect of these proteins on the functionality of HDL is the topic of ongoing research.

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Role of apoA-I, ABCA1, LCAT, and SR-BI in the biogenesis of HDL

2006

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The concentration, composition, shape, and size of plasma high-density lipoprotein (HDL) are determined by numerous proteins that influence its biogenesis, remodeling, and catabolism. The discoveries of the HDL receptor (scavenger receptor class B type I, SR-BI) and the ABCA1 (ATP-binding cassette transporter A1) lipid transporter provided two missing links that were necessary to understand the biogenesis and some of the functions of HDL. Existing data indicate that functional interactions between apoA-I and ABCA1 are necessary for the initial lipidation of apoA-I. Through a series of intermediate steps, lipidated apoA-I proceeds to form discoidal HDL particles that can be converted to spherical particles by the action of lecithin:cholesterol acyltransferase (LCAT). Discoidal and spherical HDL can interact functionally with SR-BI and these interactions lead to selective lipid uptake and net efflux of cholesterol and thus remodel HDL. Defective apoA-I/ABCA1 interactions prevent lipidation of apoA-I that is necessary for the formation of HDL particles. In the same way, specific mutations in apoA-I or LCAT prevent the conversion of discoidal to spherical HDL particles. The interactions of lipid-bound apoA-I with SR-BI are affected in vitro by specific mutations in apoA-I or SR-BI. Furthermore, deficiency of SR-BI affects the lipid and apolipoprotein composition of HDL and is associated with increased susceptibility to atherosclerosis. Here we review the current status of the pathway of HDL biogenesis and mutations in apoA-I, ABCA1, and SR-BI that disrupt different steps of the pathway and may lead to dyslipidemia and atherosclerosis in mouse models. The phenotypes generated in experimental mouse models for apoA-I, ABCA1, LCAT, SR-BI, and other proteins of the HDL pathway may facilitate early diagnosis of similar phenotypes in the human population and provide guidance for proper treatment.

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Lymphocytes Are Not Required for the Rapid Onset of Coronary Heart Disease in Scavenger Receptor Class B Type I/Apolipoprotein E Double Knockout Mice

Cited by 20 publications

References 52 publications

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

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

HDL Biogenesis, Remodeling, and Catabolism

Role of apoA-I, ABCA1, LCAT, and SR-BI in the biogenesis of HDL

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