gw-4869 and Atherosclerosis

We reported previously that increased acid sphingomyelinase (ASMase)-catalyzed hydrolysis of sphingomyelin, which leads to increases in ceramide and sphingosine 1 phosphate (S1P), played a key role in the synergistic upregulation of proinflammatory cytokines by palmitic acid (PA), a major saturated fatty acid, and lipopolysaccharide (LPS) in macrophages. Since macrophages are vital players in nonalcoholic steatohepatitis (NASH) and atherosclerosis, we assessed the effect of ASMase inhibition on NASH and atherosclerosis cooperatively induced by high-PA-containing high-fat diet (HP-HFD) and LPS in LDL receptor-deficient (LDLR-/-) mice. LDLR-/- mice were fed HP-HFD, injected with low dose of LPS and treated with or without the ASMase inhibitor amitriptyline. The neutral sphingomyelinase inhibitor GW4869 was used as control. Metabolic study showed that both amitriptyline and GW4869 reduced glucose, lipids, and insulin resistance. Histological analysis and Oil Red O staining showed that amitriptyline robustly reduced hepatic steatosis while GW4869 had modest effects. Interestingly, immunohistochemical study showed that amitriptyline, but not GW4869, strongly reduced hepatic inflammation. Furthermore, results showed that both amitriptyline and GW4869 attenuated atherosclerosis. To elucidate the underlying mechanisms whereby amitriptyline inhibited both NASH and atherosclerosis, but GW4869 only inhibited atherosclerosis, we found that amitriptyline, but not GW4869, downregulated proinflammatory cytokines in macrophages. Finally, we found that inhibition of sphingosine 1 phosphate production is a potential mechanism whereby amitriptyline inhibited proinflammatory cytokines. Collectively, this study showed that amitriptyline inhibited NASH and atherosclerosis through modulation of sphingolipid metabolism in LDLR-/- mice, indicating that sphingolipid metabolism in macrophages plays a crucial role in the linkage of NASH and atherosclerosis.

Topics: Amitriptyline; Aniline Compounds; Animals; Atherosclerosis; Benzylidene Compounds; Blood Glucose; Cytokines; Diet, High-Fat; Down-Regulation; Enzyme Inhibitors; Insulin Resistance; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Receptors, LDL; Sphingolipids; Sphingomyelin Phosphodiesterase

Atherosclerosis is a chronic multifactorial and inflammatory disease of large and medium arteries and the leading cause of cardiovascular diseases worldwide. The aim of this study was to investigate whether and how the nSMase2 (type 2-neutral sphingomyelinase), a key enzyme of sphingolipid metabolism, may contribute to the development of atherosclerotic lesions.. The role of nSMase2 in atherosclerosis was investigated in. The genetic deficiency or inhibition of nSMase2 strongly decreases the development of atherosclerotic lesions in

Topics: Aniline Compounds; Animals; Anti-Inflammatory Agents; Aorta; Aortic Diseases; Atherosclerosis; Benzylidene Compounds; Disease Models, Animal; Endothelial Cells; Enzyme Inhibitors; Inflammation; Inflammation Mediators; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C57BL; Mice, Knockout, ApoE; NF-E2-Related Factor 2; Plaque, Atherosclerotic; RAW 264.7 Cells; Signal Transduction; Sphingomyelin Phosphodiesterase