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

Abstract

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and apoE exhibit extensive aortic sinus atherosclerosis (advanced plaques with fibrous caps 2 that contain macrophages [unpublished data, 2005]), occlusive coronary arterial atherosclerosis (cellular and acellular plaques containing lipid [including cholesterol clefts], collagen, and fibrin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 ...

Apolipoprotein E Knockout Models

“…However, the double apo E/SR-BI KO mice have increased cholesterol (serum cholesterol levels 800 to 1000 mg/dl) and accelerated atherosclerosis ( 4 weeks of age) [119]. Yu et al [120] found that macrophage apo E promotes reductions in serum cholesterol levels, improves HDL subpopulations, provides extensive protection from atherosclerotic lesion development, and prevents premature death in double apo E/SR-BI KO mice [120,121]. Furthermore, treatment of SR-BI/apo E KO mice with probucol (a lipid lowering drug) extended their lives (from 6 to 36 weeks) and essentially reversed all early-onset CHD-associated anatomical, functional, cellular and biochemical pathology [118].…”

FoxO transcription factors are required for hepatic HDL cholesterol clearance

“…Studies show that (a) HL is a liver-secreted enzyme that hydrolyzes triglycerides and phospholipids and is involved in processing large lipid-rich HDL into smaller HDL particles (18), and (b) the ligand-binding activity of HL may mediate interactions of lipoproteins with SR-BI or the plasma membrane, thus facilitating selective HDL-CE uptake (19)(20)(21)(22)(23)(24). As such, mice lacking expression of either SR-BI or HL have elevated levels of HDL-C and impaired HDL-C clearance by hepatocytes (14,(25)(26)(27)(28).…”

Influence of HDL-cholesterol-elevating drugs on the in vitro activity of the HDL receptor SR-BI

“…The influence of SR-BI on murine atherosclerosis has been examined in both the LDL receptor and apoE knockout models. Hepatic overexpression of SR-BI suppresses and loss of SR-BI expression enhances atherosclerosis in these models (45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55). The atheroprotective activity of SR-BI, even though its expression decreases plasma HDLcholesterol levels, suggests that SR-BI's role in reverse cholesterol transport (the movement of cholesterol from peripheral tissues to the liver and then excretion in the bile) may contribute to its protective activity in mice.…”