Published online before print November 15, 2004, doi: 10.1161/01.CIR.0000148370.60535.22
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(Circulation. 2004;110:3465-3471.)
© 2004 American Heart Association, Inc.
Molecular Cardiology |
Inhibition of Sphingomyelin Synthesis Reduces Atherogenesis in Apolipoprotein E–Knockout Mice
From Cardiovascular Pharmacology, Pfizer Global Research and Development, Ann Arbor, Mich.
Correspondence to Dr Robert L. Panek, Cardiovascular Pharmacology, Pfizer Global Research and Development, 2800 Plymouth Rd, Ann Arbor, MI 48105. E-mail robert.panek{at}pfizer.com
Received April 28, 2004; revision received September 21, 2004; accepted September 30, 2004.
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.
Methods and 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 ß-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.
Key Words: sphingomyelin • inhibitors • cholesterol • lipoproteins • atherosclerosis
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