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Inhibition of sphingomyelin synthesis reduces atherogenesis in apolipoprotein E-knockout mice.
Circulation. 2004 Nov 30; 110(22):3465-71.Circ

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.

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 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+Show Affiliations

Cardiovascular Pharmacology, Pfizer Global Research and Development, Ann Arbor, Mich 48105, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15545514

Citation

Park, Tae-Sik, et al. "Inhibition of Sphingomyelin Synthesis Reduces Atherogenesis in Apolipoprotein E-knockout Mice." Circulation, vol. 110, no. 22, 2004, pp. 3465-71.
Park TS, Panek RL, Mueller SB, et al. Inhibition of sphingomyelin synthesis reduces atherogenesis in apolipoprotein E-knockout mice. Circulation. 2004;110(22):3465-71.
Park, T. S., Panek, R. L., Mueller, S. B., Hanselman, J. C., Rosebury, W. S., Robertson, A. W., Kindt, E. K., Homan, R., Karathanasis, S. K., & Rekhter, M. D. (2004). Inhibition of sphingomyelin synthesis reduces atherogenesis in apolipoprotein E-knockout mice. Circulation, 110(22), 3465-71.
Park TS, et al. Inhibition of Sphingomyelin Synthesis Reduces Atherogenesis in Apolipoprotein E-knockout Mice. Circulation. 2004 Nov 30;110(22):3465-71. PubMed PMID: 15545514.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of sphingomyelin synthesis reduces atherogenesis in apolipoprotein E-knockout mice. AU - Park,Tae-Sik, AU - Panek,Robert L, AU - Mueller,Sandra Bak, AU - Hanselman,Jeffrey C, AU - Rosebury,Wendy S, AU - Robertson,Andrew W, AU - Kindt,Erick K, AU - Homan,Reynold, AU - Karathanasis,Sotirios K, AU - Rekhter,Mark D, Y1 - 2004/11/15/ PY - 2004/11/17/pubmed PY - 2005/6/14/medline PY - 2004/11/17/entrez SP - 3465 EP - 71 JF - Circulation JO - Circulation VL - 110 IS - 22 N2 - 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 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. SN - 1524-4539 UR - https://www.unboundmedicine.com/medline/citation/15545514/Inhibition_of_sphingomyelin_synthesis_reduces_atherogenesis_in_apolipoprotein_E_knockout_mice_ L2 - https://www.ahajournals.org/doi/10.1161/01.CIR.0000148370.60535.22?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -