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Serine palmitoyltransferase inhibitor myriocin induces the regression of atherosclerotic plaques in hyperlipidemic ApoE-deficient mice.

Abstract：

:Myriocin, a potent inhibitor of serine palmitoyltransferase (SPT), has been shown to reduce plasma sphingolipids, cholesterol and triglycerides in hyperlipidemic apolipoprotein E knockout (apoE KO) mice. We hypothesized that the inhibition of sphingolipid biosynthesis modulates the composition of atherosclerotic plaque via its lipid-lowering effects. To test this hypothesis, the effect of myriocin on plasma lipids, sphingolipids and atherosclerosis progression, regression and lesion composition was investigated in apoE KO mice. Myriocin was administered to 24-week-old male apoE KO mice for 12 weeks. Myriocin-treated apoE KO mice had significant reductions in plasma total cholesterol, triglycerides, VLDL-cholesterol, ceramide, sphinganine and sphingomyelin (SM) compared to 24- and 36-week-old control mice. The ratio of SM to phosphatidylcholine (SM/PC), an independent risk factor for coronary artery disease, was also reduced by myriocin. Compared to 24- and 36-week controls, atherosclerotic lesion area and macrophage content in the aortic root and brachiocephalic arteries of myriocin-treated ApoE KO mice were reduced but there was only a slight increase in smooth muscle content. However, the content of collagen within aortic root lesions was increased in myriocin-treated apoE KO mice. In summary, the inhibition of SPT lowers plasma sphingolipids and atherogenic plasma lipids leading to the regression of pre-existing atherosclerotic lesions and to the formation of a stable plaque phenotype.

journal_name

Pharmacol Res

journal_title

Pharmacological research

authors

Park TS,Rosebury W,Kindt EK,Kowala MC,Panek RL

doi

10.1016/j.phrs.2008.06.005

subject

Has Abstract

pub_date

2008-07-01 00:00:00

pages

45-51

issue

1

eissn

1043-6618

issn

1096-1186

pii

S1043-6618(08)00109-6

journal_volume

58

pub_type

杂志文章

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