Molecular and Cellular Cardiology Program, VA New York Harbor Healthcare System, Brooklyn, NY, USA.
Arterioscler Thromb Vasc Biol. 2012 Jul;32(7):1577-84. doi: 10.1161/ATVBAHA.112.251538. Epub 2012 May 10.
Sphingomyelin synthase (SMS) catalyzes the conversion of ceramide to sphingomyelin and sits at the crossroads of sphingolipid biosynthesis. SMS has 2 isoforms: SMS1 and SMS2. Although they have the same SMS activity, they are different enzymes with distinguishable subcellular localizations and cell expression patterns. It is conceivable that these differences could yield different consequences, in terms of sphingolipid metabolism and its related atherogenesis.
We created Sms1 gene knockout mice and found that Sms1 deficiency significantly decreased plasma, liver, and macrophage sphingomyelin (59%, 45%, and 54%, respectively), but only had a marginal effect on ceramide levels. Surprisingly, we found that Sms1 deficiency dramatically increased glucosylceramide and GM3 levels in plasma, liver, and macrophages (4- to 12-fold), whereas Sms2 deficiency had no such effect. We evaluated the total SMS activity in tissues and found that Sms1 deficiency causes 77% reduction in SMS activity in macrophages, indicating SMS1 is the major SMS in macrophages. Moreover, Sms1-deficient macrophages have a significantly higher glucosylceramide synthase activity. We also found that Sms1 deficiency significantly attenuated toll-like 4 receptor-mediated nuclear factor-κB and mitogen-activated protein kinase activation after lipopolysaccharide treatment. To evaluate atherogenicity, we transplanted Sms1 knockout mouse bone marrow into low-density lipoprotein receptor knockout mice (Sms1(-/-)→Ldlr(-/-)). After 3 months on a western diet, these animals showed a significant decrease of atherosclerotic lesions in the root and the entire aorta (35% and 44%, P<0.01, respectively) and macrophage content in lesions (51%, P<0.05), compared with wild-type→Ldlr(-/-) mice.
Sms1 deficiency decreases sphingomyelin, but dramatically increases the levels of glycosphingolipids. Atherosclerosis in Sms1(-/-)→Ldlr(-/-) mice is significantly decreased.
神经酰胺合成酶 (SMS) 催化神经酰胺转化为神经鞘磷脂，处于鞘脂生物合成的交汇点。SMS 有 2 种同工酶：SMS1 和 SMS2。尽管它们具有相同的 SMS 活性，但它们是具有不同亚细胞定位和细胞表达模式的不同酶。可以想象，这些差异可能会在鞘脂代谢及其相关动脉粥样硬化形成方面产生不同的后果。
我们创建了 Sms1 基因敲除小鼠，发现 Sms1 缺乏显着降低了血浆、肝脏和巨噬细胞中的神经鞘磷脂（分别降低了 59%、45%和 54%），但对神经酰胺水平只有轻微影响。令人惊讶的是，我们发现 Sms1 缺乏显着增加了血浆、肝脏和巨噬细胞中的葡萄糖神经鞘脂和 GM3 水平（4-12 倍），而 Sms2 缺乏则没有这种作用。我们评估了组织中的总 SMS 活性，发现 Sms1 缺乏导致巨噬细胞中 SMS 活性降低 77%，表明 SMS1 是巨噬细胞中的主要 SMS。此外，Sms1 缺乏的巨噬细胞葡萄糖神经鞘脂合酶活性显着升高。我们还发现 Sms1 缺乏显着减弱了脂多糖处理后 Toll 样受体 4 介导的核因子-κB 和丝裂原活化蛋白激酶的激活。为了评估动脉粥样硬化形成，我们将 Sms1 敲除小鼠的骨髓移植到低密度脂蛋白受体敲除小鼠（Sms1(-/-)→Ldlr(-/-)）中。在西方饮食 3 个月后，与野生型→Ldlr(-/-)小鼠相比，这些动物的根部和整个主动脉的动脉粥样硬化病变明显减少（分别减少 35%和 44%，P<0.01），病变中的巨噬细胞含量减少（减少 51%，P<0.05）。
Sms1 缺乏会降低神经鞘磷脂，但会显着增加糖鞘脂的水平。Sms1(-/-)→Ldlr(-/-)小鼠的动脉粥样硬化明显减少。
