Affiliation:
1. From the Molecular and Cellular Cardiology Program, VA New York Harbor Healthcare System, Brooklyn, NY (Z.L., X.C.J.); Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY (Z.L., Y.F., J.L., Y.L., C.H., X.C.J.); Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, IN (M-S.K., G.C.); Department of Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, South Korea (T.P.); and Department of Cardiology,...
Abstract
Objective—
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.
Methods and Results—
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.
Conclusion—
Sms1
deficiency decreases sphingomyelin, but dramatically increases the levels of glycosphingolipids. Atherosclerosis in
Sms1
–/–
→Ldlr
–/–
mice is significantly decreased.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
97 articles.
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