Selective Reduction in the Sphingomyelin Content of Atherogenic Lipoproteins Inhibits Their Retention in Murine Aortas and the Subsequent Development of Atherosclerosis

Abstract

Objective The sphingolipid de novo synthesis pathway is considered a promising target for pharmacological intervention in atherosclerosis. However, its potential is hampered by the fact that the substance’s atherogenic mechanism is not completely understood. To unravel the complex mechanisms, we utilized the sphingomyelin synthase 2 (Sms2) gene knockout approach to test our hypothesis that selectively decreasing plasma lipoprotein SM, can play an important role in preventing atherosclerosis. Methods and Results We prepared Sms2 and Apoe double knockout (KO) mice. They showed a significant decrease in plasma lipoprotein SM levels (35%, P<0.01) and a significant increase in ceramide and dihydroceramide levels (87.5 and 27%, P<0.01, respectively), but no significant changes in other tested sphingolipids, cholesterol, and triglyceride. Non-HDL lipoproteins from the double KO mice showed a reduction of SM but not cholesterol and displayed a less tendency toward aortic sphingomyelinase-mediated lipoprotein aggregation in vitro and retention in aortas in vivo, compared to controls. More important, at age 19 weeks, Sms2 KO/Apoe KO mice showed a significant reduction in atherosclerotic lesions of the aortic arch and root (52%, P<0.01), compared to controls. We also found that the Sms2 KO/Apoe KO brachiocephalic artery (BCA) contained significantly less SM, ceramide, free cholesterol, and cholesteryl ester (35, 32, 58, and 60%, P<0.01, respectively), than that of Apoe KO BCA. Conclusions Decreasing plasma SM levels through decreasing SMS2 activity could become a promising treatment for atherosclerosis.

Molecular Biology of Atherosclerosis

“…252% Sphingomyelin synthase 2 (SMS2) KO mice had lower sphingomyelin content in nonHDL lipoproteins, less aggregation of these lipoproteins upon exposure to sphingomyelinase, and decreased lipoproteins in the aortic wall (497). Similar results with macrophage-only SMS2 deficiency in LDLR Ϫ/Ϫ mice (1058).…”

Impact of Sphingomyelin Synthase 1 Deficiency on Sphingolipid Metabolism and Atherosclerosis in Mice

“…It is conceivable that different cellular localizations could yield different consequences, in terms of sphingolipid metabolism and its related atherogenesis. We found that Sms2 deficiency significantly decreases SM levels in the blood, the liver and macrophages, but has only a marginal influence on other sphingolipid levels (2), and Sms2 total deficiency decreases atherosclerosis in mice (3). Although we have reported that macrophage Sms2 deficiency has antiatherogenic properties, SMS2 is only responsible for about 16% of total activity in macrophages (4).…”

Inhibitors of the sphingomyelin cycle: Sphingomyelin synthases and sphingomyelinases

“…Moreover, SMS2 -/-mice on a high fat diet showed increased plasma ApoE levels and cholesterol efflux from macrophages (Liu et al, 2009). In another study using double knockout mice for SMS2 and apolipoprotein E (Apo E), the double knock-outs presented less plasma SM than the single ApoE knock-out mice and an increase in Cer and dihydroCer, reduction of SM in non-HDLs, less retention of non-HDLs in aortas and an overall reduction of atherosclerotic lesions (Fan et al, 2010). In addition, SMS1 and SMS2 deficiency in macrophages in LDLr −/− mice fed a western diet decreased the number of atherosclerotic lesions, and macrophages and necrosis in the remaining lesions (Liu and Stainier, 2012).…”