Little is known about the role of glycosphingoiipids (GSL) in atherosclerosis, which contributes to cardiovascular disease (CVD) and death in ~50% of the population, in the western world. We have observed that the level of a GSL;lactosylceramide (LacCer) and the activity of LacCer synthase (LCS) is increased in human atherosclerotic plaques, as compared to visibly normal tissue. Our preliminary studies also show that atherosclerosis and a marked increase in the level of blood cholesterol can be reveresed by a GSL synthesis inhibitor (D-1-phenyl-2-decanoylamino-3-morpholino-1-propanol;D-PDMP) in a dietary model of hyperlipidemia in rabbits. Our overall goal is to determine whether inhibiting GSL synthesis can ameliorate atherosclerosis in an apolipoprotien E(apoE-/-) mouse model of hyperlipidemia /atherosclerosis. And to determine whether LCS mass can serve as a prognostic marker in CVD.
Our specific aims are: 1. To determine the efficacy of D-PDMP in regulating atherosclerosis in apoE-/- mice; herein, the efficacy of D-PDMP in preventing and interfering with atherosclerosis will be examined in mice fed a hyperlipidemic diet, and the following will be measured: cadiac function, carotid intima media thickeness, arterial stiffness, and lipid and lipoprotiens. 2. To determine the molecular mechansim(s) by which D-PDMP regulates atherosclerosis;proteins affecting GSL and cholesterol homeostasis contributing to cell proliferation adhesion and angiogenesis will be measured. 3.To determine the specific roles of Lactosylceramide and LCS in atherosclerosis. We will synthesize novel LCS inhibitors and determine their efficacy in preventing /interfering with atherosclerosis. 4. Quantify the mass of LCS and assess post- transcriptional modification in the heart and artery in normal and atherosclerotic mice. We will develop novel ELISA assays and use mass spectrometry to determine LCS mass and post transcriptional modifiactions. The proposed studies will definitely establish that inhibiting GSL synthesis can inhibit atherosclerosis. It will also prove that LCS can be a novel target for developming drugs to ameliorate CVD and related diseases. Finally, these studies will change our mind-set with regard to the role of GSL in health and CVD.

Public Health Relevance

Although much is known about the role of cholesterol in heart disease, our knowledge about the role of glycosphingoiipids in this disease has lagged behind. Herein, we propse to test the hypothesis that inhibiting glycosphingolipid synthesis can decrease blood levels of cholesterol, and ameliorate atherosclerosis and heart disease in animal models. Our studies will lay the foundation for application of novel drug therapy to amfillnratft hfiart riisfiasft in man

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-H)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
United States
Zip Code
Zhu, Guangshuo; Groneberg, Dieter; Sikka, Gautam et al. (2015) Soluble guanylate cyclase is required for systemic vasodilation but not positive inotropy induced by nitroxyl in the mouse. Hypertension 65:385-92
Bullen, John W; Balsbaugh, Jeremy L; Chanda, Dipanjan et al. (2014) Cross-talk between two essential nutrient-sensitive enzymes: O-GlcNAc transferase (OGT) and AMP-activated protein kinase (AMPK). J Biol Chem 289:10592-606
Wang, Xiangchun; Chen, Jing; Li, Qing Kay et al. (2014) Overexpression of ? (1,6) fucosyltransferase associated with aggressive prostate cancer. Glycobiology 24:935-44
Hardivillé, Stéphan; Hart, Gerald W (2014) Nutrient regulation of signaling, transcription, and cell physiology by O-GlcNAcylation. Cell Metab 20:208-13
Hascall, Vincent C; Wang, Aimin; Tammi, Markku et al. (2014) The dynamic metabolism of hyaluronan regulates the cytosolic concentration of UDP-GlcNAc. Matrix Biol 35:14-7
Aiyetan, Paul; Zhang, Bai; Chen, Lily et al. (2014) M2Lite: An Open-source, Light-weight, Pluggable and Fast Proteome Discoverer MSF to mzIdentML Tool. J Bioinform 1:40-49
Harlan, Robert; Zhang, Hui (2014) Targeted proteomics: a bridge between discovery and validation. Expert Rev Proteomics 11:657-61
Seo, Kinya; Rainer, Peter P; Lee, Dong-Ik et al. (2014) Hyperactive adverse mechanical stress responses in dystrophic heart are coupled to transient receptor potential canonical 6 and blocked by cGMP-protein kinase G modulation. Circ Res 114:823-32
Liu, Yansheng; Chen, Jing; Sethi, Atul et al. (2014) Glycoproteomic analysis of prostate cancer tissues by SWATH mass spectrometry discovers N-acylethanolamine acid amidase and protein tyrosine kinase 7 as signatures for tumor aggressiveness. Mol Cell Proteomics 13:1753-68
Sun, Shisheng; Zhou, Jian-Ying; Yang, Weiming et al. (2014) Inhibition of protein carbamylation in urea solution using ammonium-containing buffers. Anal Biochem 446:76-81

Showing the most recent 10 out of 40 publications