Endothelial injury promotes the development of atherosclerosis at the site of disturbed flow. Sphingosine-1-phosphate (S1P), produced by sphingolipid metabolism, is a secreted lipid mediator that interacts with G protein-coupled receptors, named S1P1-5. Locally produced and circulating S1P activate S1P receptors, particularly S1P1 the most abundant in the endothelium, to maintain vascular homeostasis. Altered sphingolipid metabolism and S1P signaling has been implicated in vascular disease, including coronary artery diseases (CAD). The current grant led to several advances. First, we discovered a novel mechanism by which endothelial sphingolipid biosynthesis is regulated. Nogo-B, a membrane protein of the ER, highly expressed in blood vessels, binds to and inhibits serine palmitoyltransferase (SPT), the rate-limiting enzyme of the de novo sphingolipid production. Second, we revealed that Nogo-B/SPT interaction downregulates local S1P signaling contributing to inflammation, hypertension and heart failure. Third, we found that inflammatory stimuli and ox-LDL induce Nogo-B phosphorylation, which further inhibits SPT activity contributing to endothelial injury. Fourth, following TNF-?, the N-terminus of Nogo-B is cleaved and translocates to the nucleus to impact endothelial transcriptome. Our long-term goal is to understand how Nogo-B regulates local sphingolipid signaling and its impact on coronary functions in the pathogenesis of CAD. Our hypothesis is that Nogo-B controls endothelial-derived S1P signaling, which is a key regulator of vascular homeostasis and disease- thereby influencing coronary plaque progression. Mechanistically, we hypothesize that Nogo-B promotes vascular inflammation and diseases via two major mechanisms; SPT inhibition, thus disrupting locally-derived S1P signaling, and the activation of gene profile. The rational is that the discovery of new mechanisms regulating endothelial inflammation will provide potential therapeutic targets for CAD. For the renewal, we propose to: 1) Investigate the role of endothelial Nogo-B in the susceptibility of mice to coronary atherosclerosis; 2) Determine the importance of endothelial S1P signaling and its role as downstream effector of Nogo-B in the onset of coronary atherosclerosis; 3) Dissecting the mechanism of Nogo-B signaling in myocardial endothelial injury. This contribution is significant since will identify novel targets for the treatment of CAD, especially since available therapies have been only partially successful, and beyond the statins, there are currently no effective pharmacological strategies that effectively address vascular inflammation. The proposed research is innovative because we investigate the effects of altered sphingolipid homeostasis and S1P signaling on the progression of coronary atherosclerosis, by using a novel mouse model of CAD and myocardial infarction that better recapitulates the human disease, a heretofore-unexamined process.

Public Health Relevance

The proposed research is relevant to the public health because CAD remains a top determinant of mortality, and represents a major economic burden based on 2017 report of AHA. From this study, we will understand the role for Nogo-B-dependent sphingolipid metabolism and S1P signaling in atherosclerosis, and this finding will provide a framework for target and drug discovery directed to ameliorate vascular inflammation in CAD and other CV conditions.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Vascular Cell and Molecular Biology Study Section (VCMB)
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Gao, Yunling
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Weill Medical College of Cornell University
Schools of Medicine
New York
United States
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Xu, Ren; Yallowitz, Alisha; Qin, An et al. (2018) Targeting skeletal endothelium to ameliorate bone loss. Nat Med 24:823-833
Swendeman, Steven L; Xiong, Yuquan; Cantalupo, Anna et al. (2017) An engineered S1P chaperone attenuates hypertension and ischemic injury. Sci Signal 10:
Cantalupo, Anna; Gargiulo, Antonella; Dautaj, Elona et al. (2017) S1PR1 (Sphingosine-1-Phosphate Receptor 1) Signaling Regulates Blood Flow and Pressure. Hypertension 70:426-434
Christensen, Pernille M; Liu, Catherine H; Swendeman, Steven L et al. (2016) Impaired endothelial barrier function in apolipoprotein M-deficient mice is dependent on sphingosine-1-phosphate receptor 1. FASEB J 30:2351-9
Sasset, Linda; Zhang, Yi; Dunn, Teresa M et al. (2016) Sphingolipid De Novo Biosynthesis: A Rheostat of Cardiovascular Homeostasis. Trends Endocrinol Metab 27:807-819
Zhang, Yi; Huang, Yan; Cantalupo, Anna et al. (2016) Endothelial Nogo-B regulates sphingolipid biosynthesis to promote pathological cardiac hypertrophy during chronic pressure overload. JCI Insight 1:
Cantalupo, Anna; Di Lorenzo, Annarita (2016) S1P Signaling and De Novo Biosynthesis in Blood Pressure Homeostasis. J Pharmacol Exp Ther 358:359-70
Cantalupo, Anna; Zhang, Yi; Kothiya, Milankumar et al. (2015) Nogo-B regulates endothelial sphingolipid homeostasis to control vascular function and blood pressure. Nat Med 21:1028-1037