Inhibition of sphingomyelin synthesis reduces atherogenesis in apolipoprotein E-knockout mice.
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.
Park
Tae-Sik
TS
Cardiovascular Pharmacology, Pfizer Global Research and Development, Ann Arbor, Mich 48105, USA.
Panek
Robert L
RL
Mueller
Sandra Bak
SB
Hanselman
Jeffrey C
JC
Rosebury
Wendy S
WS
Robertson
Andrew W
AW
Kindt
Erick K
EK
Homan
Reynold
R
Karathanasis
Sotirios K
SK
Rekhter
Mark D
MD
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
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