This Article Full Text Full Text (PDF) All Versions of this Article: 110/22/3465    most recent 01.CIR.0000148370.60535.22v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Park, T.-S. Articles by Rekhter, M. D. Search for Related Content PubMed PubMed Citation Articles by Park, T.-S. Articles by Rekhter, M. D. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CHOLESTEROL Related Collections Lipid and lipoprotein metabolism Related Article

(Circulation. 2004;110:3465-3471.)
© 2004 American Heart Association, Inc.

Molecular Cardiology

Inhibition of Sphingomyelin Synthesis Reduces Atherogenesis in Apolipoprotein E–Knockout Mice

Tae-Sik Park, PhD; Robert L. Panek, PhD; Sandra Bak Mueller, MS; Jeffrey C. Hanselman, BS; Wendy S. Rosebury, HT (ASCP); Andrew W. Robertson, HT (ASCP); Erick K. Kindt, BS, MBA; Reynold Homan, PhD; Sotirios K. Karathanasis, PhD; Mark D. Rekhter, MD, PhD

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

Related Article:

Sphingolipids and Atherosclerosis: A Mechanistic Connection? A Therapeutic Opportunity?

Ira Tabas
Circulation 2004 110: 3400-3401. [Extract] [Full Text]

This article has been cited by other articles:

				E. N. Glaros, W. S. Kim, K.-A. Rye, J. A. Shayman, and B. Garner Reduction of plasma glycosphingolipid levels has no impact on atherosclerosis in apolipoprotein E-null mice J. Lipid Res., August 1, 2008; 49(8): 1677 - 1681. [Abstract] [Full Text] [PDF]

				W. L. Holland and S. A. Summers Sphingolipids, Insulin Resistance, and Metabolic Disease: New Insights from in Vivo Manipulation of Sphingolipid Metabolism Endocr. Rev., June 1, 2008; 29(4): 381 - 402. [Abstract] [Full Text] [PDF]

				C. Shah, G. Yang, I. Lee, J. Bielawski, Y. A. Hannun, and F. Samad Protection from High Fat Diet-induced Increase in Ceramide in Mice Lacking Plasminogen Activator Inhibitor 1 J. Biol. Chem., May 16, 2008; 283(20): 13538 - 13548. [Abstract] [Full Text] [PDF]

				E. N. Glaros, W. S. Kim, C. M. Quinn, W. Jessup, K.-A. Rye, and B. Garner Myriocin slows the progression of established atherosclerotic lesions in apolipoprotein E gene knockout mice J. Lipid Res., February 1, 2008; 49(2): 324 - 331. [Abstract] [Full Text] [PDF]

				R. Klingenberg, J.-R. Nofer, M. Rudling, F. Bea, E. Blessing, M. Preusch, H. J. Grone, H. A. Katus, G. K. Hansson, and T. J. Dengler Sphingosine-1-Phosphate Analogue FTY720 Causes Lymphocyte Redistribution and Hypercholesterolemia in ApoE-Deficient Mice Arterioscler. Thromb. Vasc. Biol., November 1, 2007; 27(11): 2392 - 2399. [Abstract] [Full Text] [PDF]

				A. Kontush, P. Therond, A. Zerrad, M. Couturier, A. Negre-Salvayre, J. A. de Souza, S. Chantepie, and M. J. Chapman Preferential Sphingosine-1-Phosphate Enrichment and Sphingomyelin Depletion Are Key Features of Small Dense HDL3 Particles: Relevance to Antiapoptotic and Antioxidative Activities Arterioscler. Thromb. Vasc. Biol., August 1, 2007; 27(8): 1843 - 1849. [Abstract] [Full Text] [PDF]

				C. Schafer, A. Parlesak, J. Eckoldt, C. Bode, J. C. Bode, W. Marz, and K. Winkler Beyond HDL-cholesterol increase: phospholipid enrichment and shift from HDL3 to HDL2 in alcohol consumers J. Lipid Res., July 1, 2007; 48(7): 1550 - 1558. [Abstract] [Full Text] [PDF]

				C. L. Jackson, M. R. Bennett, E. A.L. Biessen, J. L. Johnson, and R. Krams Assessment of Unstable Atherosclerosis in Mice Arterioscler. Thromb. Vasc. Biol., April 1, 2007; 27(4): 714 - 720. [Abstract] [Full Text] [PDF]

				F. Samad, K. D. Hester, G. Yang, Y. A. Hannun, and J. Bielawski Altered Adipose and Plasma Sphingolipid Metabolism in Obesity: A Potential Mechanism for Cardiovascular and Metabolic Risk Diabetes, September 1, 2006; 55(9): 2579 - 2587. [Abstract] [Full Text] [PDF]

				J. Dong, J. Liu, B. Lou, Z. Li, X. Ye, M. Wu, and X.-C. Jiang Adenovirus-mediated overexpression of sphingomyelin synthases 1 and 2 increases the atherogenic potential in mice J. Lipid Res., June 1, 2006; 47(6): 1307 - 1314. [Abstract] [Full Text] [PDF]

				J. C. Nelson, X.-C. Jiang, I. Tabas, A. Tall, and S. Shea Plasma Sphingomyelin and Subclinical Atherosclerosis: Findings from the Multi-Ethnic Study of Atherosclerosis Am. J. Epidemiol., May 15, 2006; 163(10): 903 - 912. [Abstract] [Full Text] [PDF]

				M. R. Hojjati and X.-C. Jiang Rapid, specific, and sensitive measurements of plasma sphingomyelin and phosphatidylcholine J. Lipid Res., March 1, 2006; 47(3): 673 - 676. [Abstract] [Full Text] [PDF]

				S. L. Karackattu, B. Trigatti, and M. Krieger Hepatic Lipase Deficiency Delays Atherosclerosis, Myocardial Infarction, and Cardiac Dysfunction and Extends Lifespan in SR-BI/Apolipoprotein E Double Knockout Mice Arterioscler. Thromb. Vasc. Biol., March 1, 2006; 26(3): 548 - 554. [Abstract] [Full Text] [PDF]

				A. Nilsson and R.-D. Duan Absorption and lipoprotein transport of sphingomyelin J. Lipid Res., January 1, 2006; 47(1): 154 - 171. [Abstract] [Full Text] [PDF]

				K. J. Williams and I. Tabas Lipoprotein Retention--and Clues for Atheroma Regression Arterioscler. Thromb. Vasc. Biol., August 1, 2005; 25(8): 1536 - 1540. [Abstract] [Full Text] [PDF]

				M. R. Hojjati, Z. Li, H. Zhou, S. Tang, C. Huan, E. Ooi, S. Lu, and X.-C. Jiang Effect of Myriocin on Plasma Sphingolipid Metabolism and Atherosclerosis in apoE-deficient Mice J. Biol. Chem., March 18, 2005; 280(11): 10284 - 10289. [Abstract] [Full Text] [PDF]

				I. Tabas Sphingolipids and Atherosclerosis: A Mechanistic Connection? A Therapeutic Opportunity? Circulation, November 30, 2004; 110(22): 3400 - 3401. [Full Text] [PDF]