thermozymocidin and Arteriosclerosis

Myriocin, a potent inhibitor of serine palmitoyltransferase (SPT), has been shown to reduce plasma sphingolipids, cholesterol and triglycerides in hyperlipidemic apolipoprotein E knockout (apoE KO) mice. We hypothesized that the inhibition of sphingolipid biosynthesis modulates the composition of atherosclerotic plaque via its lipid-lowering effects. To test this hypothesis, the effect of myriocin on plasma lipids, sphingolipids and atherosclerosis progression, regression and lesion composition was investigated in apoE KO mice. Myriocin was administered to 24-week-old male apoE KO mice for 12 weeks. Myriocin-treated apoE KO mice had significant reductions in plasma total cholesterol, triglycerides, VLDL-cholesterol, ceramide, sphinganine and sphingomyelin (SM) compared to 24- and 36-week-old control mice. The ratio of SM to phosphatidylcholine (SM/PC), an independent risk factor for coronary artery disease, was also reduced by myriocin. Compared to 24- and 36-week controls, atherosclerotic lesion area and macrophage content in the aortic root and brachiocephalic arteries of myriocin-treated ApoE KO mice were reduced but there was only a slight increase in smooth muscle content. However, the content of collagen within aortic root lesions was increased in myriocin-treated apoE KO mice. In summary, the inhibition of SPT lowers plasma sphingolipids and atherogenic plasma lipids leading to the regression of pre-existing atherosclerotic lesions and to the formation of a stable plaque phenotype.

Topics: Animals; Apolipoproteins E; Arteriosclerosis; Cholesterol; Disease Progression; Fatty Acids, Monounsaturated; Hyperlipidemias; Hypolipidemic Agents; Male; Mice; Mice, Knockout; Serine C-Palmitoyltransferase; Sphingolipids; Triglycerides

Sphingolipids play a very important role in cell membrane formation, signal transduction, and plasma lipoprotein metabolism, all of which may well have an impact on the development of atherosclerosis. To investigate the relationship between sphingolipid metabolism and atherosclerosis, we utilized myriocin to inhibit mouse serine palmitoyl-CoA transferase (SPT), the key enzyme for sphingolipid biosynthesis. We injected 8-week-old apoE-deficient mice with myriocin (0.3 mg/kg/every other day, intraperitoneal) for 60 days. On a chow diet, myriocin treatment caused a significant decrease (50%) in liver SPT activity (p < 0.001), significant decreases in plasma sphingomyelin, ceramide, and sphingosine-1-phosphate levels (54, 32, and 73%, respectively) (p < 0.0001), and a significant increase in plasma phosphatidylcholine levels (91%) (p < 0.0001). Plasma total cholesterol and triglyceride levels demonstrated no significant changes, but there was a significant decrease in atherosclerotic lesion area (42% in root and 36% in en face assays) (p < 0.01). On a high fat diet, myriocin treatment caused marked decreases in plasma sphingomyelin, ceramide, and sphingosine-1-phosphate levels (59, 66, and 81%, respectively) (p < 0.0001), and a marked increase in plasma phosphatidylcholine levels (100%) (p < 0.0001). Total cholesterol and triglyceride demonstrated no significant changes, but there was a significant decrease in atherosclerotic lesion area (39% in root and 37% in en face assays) (p < 0.01). These results indicate that, apart from cholesterol levels, sphingolipids have an effect on atherosclerotic development and that SPT has proatherogenic properties. Thus, inhibition of SPT activity could be an alternative treatment for atherosclerosis.

Topics: Acyltransferases; Animal Feed; Animals; Aorta; Apolipoproteins E; Arteriosclerosis; Ceramides; Cholesterol; Fatty Acids, Monounsaturated; Immunosuppressive Agents; Lipid Metabolism; Lipids; Lipoproteins; Lysophospholipids; Mass Spectrometry; Mice; Mice, Knockout; Phosphatidylcholines; Serine C-Palmitoyltransferase; Signal Transduction; Sphingolipids; Sphingosine; Time Factors; Triglycerides

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.

Topics: Acyltransferases; Animals; Aorta; Aortic Diseases; Apolipoproteins E; Arteriosclerosis; Cholesterol; Chromatography, High Pressure Liquid; Diet, Atherogenic; Drug Evaluation, Preclinical; Enzyme Induction; Fatty Acids, Monounsaturated; Hyperlipoproteinemia Type II; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phospholipids; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; RNA, Messenger; Serine C-Palmitoyltransferase; Sphingomyelins; Sphingosine; T-Lymphocytes; Triglycerides

Topics: Acyltransferases; Animals; Apolipoproteins E; Arteriosclerosis; Diet, Atherogenic; Drug Evaluation, Preclinical; Fatty Acids, Monounsaturated; Humans; Hyperlipoproteinemia Type II; Lipoproteins; Lipoproteins, HDL; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Animal; Serine C-Palmitoyltransferase; Species Specificity; Sphingolipids; Sphingomyelin Phosphodiesterase