Abstract
Sphingomyelin synthase (SMS) plays an important role in plasma atherogenic lipoprotein metabolism, inflammation, and the development of atherosclerosis. To understand whether the impaired apoB secretion and inflammation response is a direct result from lack of SMS activity, in this study, we prepared a series of compounds that inhibit SMS activity. Further, we characterized Dy105, the most potent inhibitor. We found that Dy105 treatment significantly reduces SM levels in SM-rich microdomain on cell membranes. Moreover, we found that SMS inhibition reduces apoB secretion in a human hepatoma cell line and reduces the activation of NFκB and p38, a MAP kinase, in bone marrow derived macrophages. These studies provided further evidence that SMS activity regulates atherogenic lipoprotein metabolism and inflammatory responses. Pharmacologic inhibition of SMS may be a new therapy for atherosclerosis by reducing apoB secretion, and reducing inflammation.
Highlights
In the developed countries, coronary heart disease (CHD) is the major cause of mortality
Sphingomyelin synthase (SMS) activity inhibitors Based on homology modeling and molecular dynamics simulation, we have reported a structural model of human SMS1 [32]
We found that the compound significantly decreases Huh7 cell (Fig. 2A and B) and bone marrow derived macrophages (BMM) (Fig. 2C and D) SMS activity in a dose dependent fashion
Summary
Coronary heart disease (CHD) is the major cause of mortality. Statin therapy is the main option for CHD clinical management. Statin therapy is not always responsive and sometimes patient is intolerant to this therapy [1,2,3,4,5,6]. Additional approaches are necessary to lower plasma atherogenic lipoprotein levels, and act synergistically with statins. Serum or plasma sphingomyelin (SM) is considered as a risk factor for CHD [7,8] and that SM levels are prognostic in patients with acute coronary syndrome [8]. Serum SM levels are enriched on atherogenic lipoproteins such as very low density lipoprotein (VLDL), low density lipoprotein (LDL), and chylomicron [9,10]. Subendothelial retention and aggregation of atherogenic lipoproteins play a very important role in atherogenesis [12,13]
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