title: Inhibition of sphingomyelin synthesis reduces atherogenesis in apolipoprotein E-knockout mice.
abstract: BACKGROUND
  In clinical studies, sphingomyelin (SM) plasma levels correlated with the occurrence of coronary heart disease independently of plasma cholesterol levels. We hypothesized that inhibition of SM synthesis would have antiatherogenic effects. To test this hypothesis, apolipoprotein E (apoE)-knockout (KO) mice were treated with myriocin, a potent inhibitor of serine palmitoyltransferase, the rate-limiting enzyme in SM biosynthesis.
  
  
  RESULTS
  Diet-admix treatment of apoE-KO mice with myriocin in Western diet for 12 weeks lowered SM and sphinganine plasma levels. Decreases in sphinganine and SM concentrations were also observed in the liver and aorta of myriocin-treated animals compared with controls. Inhibition of de novo sphingolipid biosynthesis reduced total cholesterol and triglyceride plasma levels. Cholesterol distribution in lipoproteins demonstrated a decrease in beta-VLDL and LDL cholesterol and an increase in HDL cholesterol. Oil red O staining of total aortas demonstrated reduction of atherosclerotic lesion coverage in the myriocin-treated group. Atherosclerotic plaque area was also reduced in the aortic root and brachiocephalic artery.
  
  
  CONCLUSIONS
  Inhibition of de novo SM biosynthesis in apoE-KO mice lowers plasma cholesterol and triglyceride levels, raises HDL cholesterol, and prevents development of atherosclerotic lesions.
authors.affiliation: Cardiovascular Pharmacology, Pfizer Global Research and Development, Ann Arbor, Mich 48105, USA.
authors.forename: Tae-Sik
authors.initials: TS
authors.lastname: Park
authors.forename: Robert L
authors.initials: RL
authors.lastname: Panek
authors.forename: Sandra Bak
authors.initials: SB
authors.lastname: Mueller
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Hanselman
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Rosebury
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Robertson
authors.forename: Erick K
authors.initials: EK
authors.lastname: Kindt
authors.forename: Reynold
authors.initials: R
authors.lastname: Homan
authors.forename: Sotirios K
authors.initials: SK
authors.lastname: Karathanasis
authors.forename: Mark D
authors.initials: MD
authors.lastname: Rekhter
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000097:blood / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000097:blood / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D002784:Cholesterol / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D004036:Diet, Atherogenic; D004353:Drug Evaluation, Preclinical; D004790:Enzyme Induction / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology / Q000627:therapeutic use*; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000150:complications / Q000201:enzymology / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010743:Phospholipids / Q000097:blood; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D051102:Serine C-Palmitoyltransferase; D013109:Sphingomyelins / Q000096:biosynthesis* / Q000097:blood; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000097:blood; D013601:T-Lymphocytes / Q000473:pathology; D014280:Triglycerides / Q000097:blood
chemical_list: D001057:Apolipoproteins E; D005229:Fatty Acids, Monounsaturated; D010743:Phospholipids; D012333:RNA, Messenger; D013109:Sphingomyelins; D014280:Triglycerides; D002784:Cholesterol; D000217:Acyltransferases; D051102:Serine C-Palmitoyltransferase; C495088:Sptlc1 protein, mouse; D013110:Sphingosine; C005682:safingol; C001996:thermozymocidin