Inhibition of atherosclerosis by the serine palmitoyl transferase inhibitor myriocin is associated with reduced plasma glycosphingolipid concentration
Inhibition of atherosclerosis by the serine palmitoyl transferase inhibitor myriocin is associated with reduced plasma glycosphingolipid concentration
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DOI：
10.1016/j.bcp.2006.12.023
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发表时间：
2007-05-01
影响因子：
5.8
通讯作者：
Garner, Brett
中科院分区：
文献类型：
--
作者：
Glaros, Elias N.;Kim, Woojin S.;Garner, Brett
鞘糖脂（GSL）被认为是潜在的致动脉粥样硬化脂质。在胆固醇或甘油三酯（TG）浓度不发生变化的情况下，抑制肝脏丝氨酸棕榈酰转移酶（SPT）可降低血浆鞘磷脂（SM）水平，从而导致载脂蛋白E基因敲除（apoE（-/-））小鼠动脉粥样硬化的减少。SPT抑制导致动脉粥样硬化减少与血浆GSL浓度降低相关的可能性尚未研究，这是本研究的主要目的。我们发现，在apoE（-/-）高脂饮食小鼠中，腹膜内注射SPT抑制剂多球壳菌素9周可抑制动脉粥样硬化。病变抑制在主动脉弓以及胸主动脉和腹主动脉的远端部位最为明显。主动脉根部的病变面积也有减少的趋势。多粒壳菌素治疗导致血浆SM和GSL浓度分别显著降低42%和25%，如通过酶法和HPLC方法评估的。此外，SM和GSL浓度显着相关，表明SPT抑制抑制这两种鞘脂的合成伴随。多球壳菌素诱导的动脉粥样硬化抑制作用与FPLC测定的血浆胆固醇或TG浓度或脂蛋白谱的变化无关。这些数据表明，血浆SM和/或GSL浓度的治疗性降低可能为动脉粥样硬化提供新的治疗方法。(c)2006年爱思唯尔公司All rights reserved.
Glycosphingolipids (GSL) have been implicated as potential atherogenic lipids. inhibition of hepatic serine palmitoyl transferase (SPT) reduces plasma sphingomyelin (SM) levels in the absence of changes in cholesterol or triglyceride (TG) concentration and this leads to a reduction of atherosclerosis in apolipoprotein-E gene knockout (apoE(-/-)) mice. The possibility that the reduced atherosclerosis resulting from SPT inhibition is associated with decreases in plasma GSL concentration has not been examined and was the primary aim of this investigation. We show that intraperitoneal delivery of the SPT inhibitor myriocin for 9 weeks inhibits atherosclerosis in apoE(-/-) mice fed a high fat diet. Lesion inhibition was most pronounced at the aortic arch and distal sites of the thoracic and abdominal aorta. There was also a trend towards a reduction in lesion area at the aortic root. Myriocin treatment resulted in significant reductions in both plasma SM and GSL concentration of 42% and 25%, as assessed by enzymatic and HPLC methods, respectively. Moreover, SM and GSL concentrations were significantly correlated, indicating that SPT inhibition suppresses the synthesis of both these sphingolipids concomitantly. The inhibition of atherosclerosis induced by myriocin was not associated with changes in plasma cholesterol or TG concentrations or lipoprotein profiles as determined by FPLC. These data indicate that therapeutic reduction of plasma SM and/or GSL concentrations may offer a novel treatment for atherosclerosis. (c) 2006 Elsevier Inc. All rights reserved.