Abstract | BACKGROUND: METHODS AND RESULTS:
Apolipoprotein E(-/-) mice (12 weeks of age; n=6) were fed regular chow or a Western diet (1.25% cholesterol, 2% fat). Mice were fed 5 or 10 mg/kg of an inhibitor of glycosphingolipid synthesis, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D- PDMP), solubilized in vehicle (5% Tween-80 in PBS); the placebo group received vehicle only. At 20 and 36 weeks of age, serial echocardiography was performed to measure aortic intima-media thickening. Aortic pulse-wave velocity measured vascular stiffness. Feeding mice a Western diet markedly increased aortic pulse-wave velocity, intima-media thickening, oxidized low-density lipoprotein, Ca(2+) deposits, and glucosylceramide and lactosylceramide synthase activity. These were dose-dependently decreased by feeding D- PDMP. In liver, D- PDMP decreased cholesterol and triglyceride levels by raising the expression of SREBP2, low-density lipoprotein receptor, HMGCo-A reductase, and the cholesterol efflux genes (eg, ABCG5, ABCG8). D- PDMP affected very-low-density lipoprotein catabolism by increasing the gene expression for lipoprotein lipase and very-low-density lipoprotein receptor. Rabbits fed a Western diet for 90 days had extensive atherosclerosis accompanied by a 17.5-fold increase in total cholesterol levels and a 3-fold increase in lactosylceramide levels. This was completely prevented by feeding D- PDMP. CONCLUSIONS:
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Authors | Subroto Chatterjee, Djahida Bedja, Sumita Mishra, Christine Amuzie, Alberto Avolio, David A Kass, Dan Berkowitz, Mark Renehan |
Journal | Circulation
(Circulation)
Vol. 129
Issue 23
Pg. 2403-13
(Jun 10 2014)
ISSN: 1524-4539 [Electronic] United States |
PMID | 24710030
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | © 2014 American Heart Association, Inc. |
Chemical References |
- Antigens, CD
- Apolipoproteins E
- Cholesterol, Dietary
- Enzyme Inhibitors
- Glucosylceramides
- Glycosphingolipids
- Lactosylceramides
- Lipoproteins, LDL
- Morpholines
- oxidized low density lipoprotein
- CDw17 antigen
- RV 538
- Calcium
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Topics |
- Animals
- Antigens, CD
(metabolism)
- Aorta
(diagnostic imaging, drug effects, metabolism)
- Apolipoproteins E
(genetics)
- Calcium
(metabolism)
- Cholesterol, Dietary
(pharmacology)
- Coronary Artery Disease
(drug therapy, genetics, metabolism)
- Diet, High-Fat
- Dose-Response Relationship, Drug
- Enzyme Inhibitors
(pharmacology)
- Gene Expression Regulation
(drug effects)
- Glucosylceramides
(metabolism)
- Glycosphingolipids
(biosynthesis, metabolism)
- Hyperlipidemias
(drug therapy, genetics, metabolism)
- Lactosylceramides
(metabolism)
- Lipoproteins, LDL
(metabolism)
- Male
- Mice
- Mice, Knockout
- Models, Cardiovascular
- Morpholines
(pharmacology)
- Pulsatile Flow
(drug effects)
- Rabbits
- Ultrasonography
- Vascular Stiffness
(drug effects)
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