Significant evidence indicates that sphingomyelin (SM) content in the aortic wall and in the plasma is closely related to atherogenesis. High SM is an independent risk factor for human coronary heart disease and is associated with human atherosclerotic plaque inflammation. We found that inhibiting serine palmitoyl- transferase, the first enzyme for SM biosynthesis reduced plasma SM and atherogenesis in mouse models. However, mechanisms are unknown, prompting further studies exploring relationships between blocking SM synthase (SMS) and atherogenesis. Two isoforms of SMS (SMS1 and SMS2) reside downstream of serine palmitoyl-transferase and catalyze the conversion of ceramide to SM. SMS1 and SMS2 activities are co- expressed in all tested tissues, including the liver, intestine, and macrophage. Thus, neither SMS1 gene knockout (KO) nor SMS2 KO approach is sufficient to evaluate the effect of SM reduction on atherosclerosis. We will use SMS1/SMS2 double KO approach in this study. Our objective is to test our hypotheses that inhibition of total SMS activity can: a) block SM bioavailability during the process of apoB-containing atherogenic lipoprotein (BLp, i.e. VLDL and chylomicron) production; b) reduce lipid absorption and attenuate inflammation by reducing SM in cell (enterocyte and macrophage) plasma membrane lipid rafts; and c) reduce atherosclerosis progression and regression without causing steatosis (SMS inhibition-mediated ceramide accumulation could suppress lipogenesis). In this study, we will use inducible global, liver-specific, and intestine-specific total SMS KO mouse models, as well as our specific SMS inhibitors.
Specific aims : 1. Evaluate effects of blocking SMS on VLDL production and catabolism. 2. Investigate the effects of blocking SMS on lipid absorption and chylomicron secretion. 3. Examine the roles of absence or inhibition of SMS in atherosclerosis progression and regression. Insights gained from the proposed studies will allow us to evaluate SMS as a target for preventing and treating atherosclerosis.

Public Health Relevance

The proposed research is intended to study the impact of sphingomyelin synthase (the key enzyme for sphingomyelin biosynthesis) difficiency on apoB-containin lipoprotein production, lipid absorption, inflammation, and atherosclerosis (progression and regression). Global, liver, and intestine inducible sphingomyelin synthase knockout mice will be used. Success with this proposal will help us to evaluate sphingomyelin synthase as a therapeutic target for the treatment atherosclerosis without causing steatosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL149730-01
Application #
9860165
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Liu, Lijuan
Project Start
2020-01-01
Project End
2023-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Suny Downstate Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
040796328
City
Brooklyn
State
NY
Country
United States
Zip Code
11203