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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:548.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

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

Sharon L. Karackattu; Bernardo Trigatti; Monty Krieger

From the Department of Biology, Massachusetts Institute of Technology, Cambridge, Mass. Current address for B.T.: Department of Biochemistry and Biomedical Sciences, McMaster University. Hamilton, Canada.

Correspondence to Monty Krieger, Room 68-483, Biology Department, Massachusetts Institute of Technology, Cambridge, MA 02139. E-mail krieger{at}mit.edu

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: 63.0±0.8 versus 46.0±0.3 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.

SR-BI/apoE double knockout (dKO) mice exhibit occlusive atherosclerotic coronary heart disease (CHD) characterized by myocardial infarctions, cardiac dysfunction, and premature death. Analysis of SR-BI/apoE/hepatic lipase (HL) triple knockout mice demonstrated that HL-deficiency reduces atherosclerosis, improves cardiac structure/function, and extends lifespan in this CHD model.

Key Words: atherosclerosis • hepatic lipase • high density lipoprotein receptor • myocardial infarction

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