Hepatic lipase deficiency delays atherosclerosis, myocardial infarction, and cardiac dysfunction and extends lifespan in SR-BI/apolipoprotein E double knockout mice.
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.


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.
Karackattu
Sharon L
SL
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Trigatti
Bernardo
B
Krieger
Monty
M
D017668:Age of Onset; D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D006332:Cardiomegaly / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D003324:Coronary Artery Disease / Q000401:mortality* / Q000473:pathology / Q000503:physiopathology*; D003331:Coronary Vessels / Q000473:pathology; D004562:Electrocardiography; D005260:Female; D008017:Life Expectancy; D008049:Lipase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000401:mortality* / Q000473:pathology / Q000503:physiopathology*; D017202:Myocardial Ischemia / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism
D001057:Apolipoproteins E; D008055:Lipids; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D008049:Lipase; C495700:Lipc protein, mouse