Park Tae-Sik, Panek Robert L, Mueller Sandra Bak, Hanselman Jeffrey C, Rosebury Wendy S, Robertson Andrew W, Kindt Erick K, Homan Reynold, Karathanasis Sotirios K, Rekhter Mark D
Cardiovascular Pharmacology, Pfizer Global Research and Development, Ann Arbor, Mich 48105, USA.
Circulation. 2004 Nov 30;110(22):3465-71. doi: 10.1161/01.CIR.0000148370.60535.22. Epub 2004 Nov 15.
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.
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.
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.
在临床研究中，鞘磷脂（SM）血浆水平与冠心病的发生相关，且独立于血浆胆固醇水平。我们推测抑制SM合成会产生抗动脉粥样硬化作用。为验证这一假设，我们用麦角硫因（一种丝氨酸棕榈酰转移酶的强效抑制剂，丝氨酸棕榈酰转移酶是SM生物合成中的限速酶）处理载脂蛋白E（apoE）基因敲除（KO）小鼠。
在西方饮食中，用麦角硫因对apoE-KO小鼠进行饮食混合处理12周，可降低血浆中SM和鞘氨醇水平。与对照组相比，在经麦角硫因处理的动物的肝脏和主动脉中也观察到鞘氨醇和SM浓度降低。从头鞘脂生物合成的抑制降低了血浆总胆固醇和甘油三酯水平。脂蛋白中的胆固醇分布显示β-VLDL和LDL胆固醇减少，HDL胆固醇增加。对整个主动脉进行油红O染色显示，麦角硫因处理组的动脉粥样硬化病变覆盖面积减少。主动脉根部和头臂动脉的动脉粥样硬化斑块面积也减小。
抑制apoE-KO小鼠从头合成SM可降低血浆胆固醇和甘油三酯水平，提高HDL胆固醇水平，并防止动脉粥样硬化病变的发展。
