Inhibition of glycosphingolipid synthesis ameliorates atherosclerosis and arterial stiffness in apolipoprotein E-/- mice and rabbits fed a high-fat and -cholesterol diet.
BACKGROUND
Glycosphingolipids, integral components of the cell membrane, have been shown to serve as messengers, transducing growth factor-initiated phenotypes. Here, we have examined whether inhibition of glycosphingolipid synthesis could ameliorate atherosclerosis and arterial stiffness in transgenic mice and rabbits.


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
Inhibition of glycosphingolipid synthesis ameliorates atherosclerosis and arterial stiffness in apolipoprotein E(-/-) mice and rabbits. Thus, inhibition of glycosphingolipid synthesis may be a novel approach to ameliorate atherosclerosis and arterial stiffness.
From the Departments of Pediatrics (S.C., S.M., C.A., M.R.), Medicine (D. Bedja, D.A.K.), and Anesthesiology and Critical Care Medicine (D. Berkowitz), Johns Hopkins University School of Medicine, Baltimore, MD; and Australian School of Advanced Medicine, Macquarie University, Sydney, Australia (D. Bedja, A.A.). Schatte2@jhmi.edu.
Subroto
S
Chatterjee
From the Departments of Pediatrics (S.C., S.M., C.A., M.R.), Medicine (D. Bedja, D.A.K.), and Anesthesiology and Critical Care Medicine (D. Berkowitz), Johns Hopkins University School of Medicine, Baltimore, MD; and Australian School of Advanced Medicine, Macquarie University, Sydney, Australia (D. Bedja, A.A.).
Djahida
D
Bedja
From the Departments of Pediatrics (S.C., S.M., C.A., M.R.), Medicine (D. Bedja, D.A.K.), and Anesthesiology and Critical Care Medicine (D. Berkowitz), Johns Hopkins University School of Medicine, Baltimore, MD; and Australian School of Advanced Medicine, Macquarie University, Sydney, Australia (D. Bedja, A.A.).
Sumita
S
Mishra
From the Departments of Pediatrics (S.C., S.M., C.A., M.R.), Medicine (D. Bedja, D.A.K.), and Anesthesiology and Critical Care Medicine (D. Berkowitz), Johns Hopkins University School of Medicine, Baltimore, MD; and Australian School of Advanced Medicine, Macquarie University, Sydney, Australia (D. Bedja, A.A.).
Christine
C
Amuzie
From the Departments of Pediatrics (S.C., S.M., C.A., M.R.), Medicine (D. Bedja, D.A.K.), and Anesthesiology and Critical Care Medicine (D. Berkowitz), Johns Hopkins University School of Medicine, Baltimore, MD; and Australian School of Advanced Medicine, Macquarie University, Sydney, Australia (D. Bedja, A.A.).
Alberto
A
Avolio
From the Departments of Pediatrics (S.C., S.M., C.A., M.R.), Medicine (D. Bedja, D.A.K.), and Anesthesiology and Critical Care Medicine (D. Berkowitz), Johns Hopkins University School of Medicine, Baltimore, MD; and Australian School of Advanced Medicine, Macquarie University, Sydney, Australia (D. Bedja, A.A.).
David A
DA
Kass
From the Departments of Pediatrics (S.C., S.M., C.A., M.R.), Medicine (D. Bedja, D.A.K.), and Anesthesiology and Critical Care Medicine (D. Berkowitz), Johns Hopkins University School of Medicine, Baltimore, MD; and Australian School of Advanced Medicine, Macquarie University, Sydney, Australia (D. Bedja, A.A.).
Dan
D
Berkowitz
From the Departments of Pediatrics (S.C., S.M., C.A., M.R.), Medicine (D. Bedja, D.A.K.), and Anesthesiology and Critical Care Medicine (D. Berkowitz), Johns Hopkins University School of Medicine, Baltimore, MD; and Australian School of Advanced Medicine, Macquarie University, Sydney, Australia (D. Bedja, A.A.).
Mark
M
Renehan
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001011:Aorta / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000494:pharmacology; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005963:Glucosylceramides / Q000378:metabolism; D006028:Glycosphingolipids / Q000096:biosynthesis* / Q000378:metabolism; D006949:Hyperlipidemias / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D007790:Lactosylceramides / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008955:Models, Cardiovascular; D009025:Morpholines / Q000494:pharmacology*; D011673:Pulsatile Flow / Q000187:drug effects; D011817:Rabbits; D014463:Ultrasonography; D059289:Vascular Stiffness / Q000187:drug effects*
D015703:Antigens, CD; D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D004791:Enzyme Inhibitors; D005963:Glucosylceramides; D006028:Glycosphingolipids; D007790:Lactosylceramides; D008077:Lipoproteins, LDL; D009025:Morpholines; C099252:oxidized low density lipoprotein; C009744:CDw17 antigen; C033110:RV 538; D002118:Calcium
atherosclerosis; glycosphingolipids; mice, knockout; molecular imaging