OBJECTIVE: We used the sphingomyelin (SM) synthase 2 (Sms2) gene knockout (KO) approach to test our hypothesis that selectively decreasing plasma lipoprotein SM can play an important role in preventing atherosclerosis. METHODS AND RESULTS: The sphingolipid de novo synthesis pathway is considered a promising target for pharmacological intervention in atherosclerosis. However, its potential is hampered because the substance's atherogenic mechanism is not completely understood. We prepared Sms2 and apolipoprotein E (Apoe) double-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%, respectively; P<0.01) but no significant changes in other tested sphingolipids, cholesterol, and triglyceride. Non-high-density lipoproteins from the double-KO mice showed a reduction of SM, but not cholesterol, and displayed less tendency toward aortic sphingomyelinase-mediated lipoprotein aggregation in vitro and retention in aortas in vivo when compared with controls. More important, at the age of 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 with controls. The Sms2 KO/Apoe KO brachiocephalic artery contained significantly less SM, ceramide, free cholesterol, and cholesteryl ester (35%, 32%, 58%, and 60%, respectively; P<0.01) than that of the Apoe KO brachiocephalic artery. CONCLUSIONS: Decreasing plasma SM levels through decreasing SMS2 activity could become a promising treatment for atherosclerosis.
OBJECTIVE: We used the sphingomyelin (SM) synthase 2 (Sms2) gene knockout (KO) approach to test our hypothesis that selectively decreasing plasma lipoprotein SM can play an important role in preventing atherosclerosis. METHODS AND RESULTS: The sphingolipid de novo synthesis pathway is considered a promising target for pharmacological intervention in atherosclerosis. However, its potential is hampered because the substance's atherogenic mechanism is not completely understood. We prepared Sms2 and apolipoprotein E (Apoe) double-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%, respectively; P<0.01) but no significant changes in other tested sphingolipids, cholesterol, and triglyceride. Non-high-density lipoproteins from the double-KO mice showed a reduction of SM, but not cholesterol, and displayed less tendency toward aortic sphingomyelinase-mediated lipoprotein aggregation in vitro and retention in aortas in vivo when compared with controls. More important, at the age of 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 with controls. The Sms2 KO/Apoe KO brachiocephalic artery contained significantly less SM, ceramide, free cholesterol, and cholesteryl ester (35%, 32%, 58%, and 60%, respectively; P<0.01) than that of the Apoe KO brachiocephalic artery. CONCLUSIONS: Decreasing plasma SM levels through decreasing SMS2 activity could become a promising treatment for atherosclerosis.
Authors: V D F de Mello; M Lankinen; U Schwab; M Kolehmainen; S Lehto; T Seppänen-Laakso; M Oresic; L Pulkkinen; M Uusitupa; A T Erkkilä Journal: Diabetologia Date: 2009-08-11 Impact factor: 10.122
Authors: S L Schissel; X Jiang; J Tweedie-Hardman; T Jeong; E H Camejo; J Najib; J H Rapp; K J Williams; I Tabas Journal: J Biol Chem Date: 1998-01-30 Impact factor: 5.157
Authors: Tae-Sik Park; Robert L Panek; Sandra Bak Mueller; Jeffrey C Hanselman; Wendy S Rosebury; Andrew W Robertson; Erick K Kindt; Reynold Homan; Sotirios K Karathanasis; Mark D Rekhter Journal: Circulation Date: 2004-11-15 Impact factor: 29.690
Authors: Young-Mi Go; Chan Woo Kim; Douglas I Walker; Dong Won Kang; Sandeep Kumar; Michael Orr; Karan Uppal; Arshed A Quyyumi; Hanjoong Jo; Dean P Jones Journal: Am J Physiol Regul Integr Comp Physiol Date: 2014-11-05 Impact factor: 3.619