Inflammatory macrophages play a key role in the development and progression of the atherosclerosis,
leading to myocardial infarction (MI). Sphingolipids are both membrane components and signaling
molecules. Ceramide and Sphingosine-1-phosphate (S1P), bioactive and interchangeable
sphingolipids, regulate a variety of cellular processes, including cell growth and survival, apoptosis, and
immune and cardiovascular functions. As cholesterol, altered sphingolipid metabolism has been
implicated in atherosclerosis. Whereas extensive studies on molecular regulation of cholesterol
biosynthesis led to the discovery of statins, widely used lowering-cholesterol drugs, how sphingolipid
biosynthesis is regulated and its pathophysiological implication are poorly understood.
In this regard, our lab discovered a novel mechanism by which sphingolipid biosynthesis is regulated in
mammals. Nogo-B, a membrane protein of the ER, binds to and inhibits serine palmitoyltransferase
(SPT), the rate-limiting enzyme of the sphingolipid de novo biosynthesis[11]. Mice lacking Nogo-B are
protected from inflammation, hypertension and heart failure, in part via endothelial S1P signaling.
Our long-term goal is to understand how sphingolipid metabolism and signaling is regulated and its
impact on coronary atherosclerosis development and progression.
Recently, we developed a novel mouse model able to develop of coronary lesions, that progress to
disruption (rupture, erosion) or occlusion leading to MI. Our hypothesis that Nogo-B downregulates SL
metabolism and signaling, mainly ceramide and S1P, to control macrophage functions in coronary
inflammation, atherosclerosis development and progression to MI. The rational is that the discovery of
new mechanisms regulating the development and progression of atherosclerosis will provide potential
therapeutic targets for coronary artery disease. Thus, we propose to: 1) investigate the role of MF
Nogo-B in the susceptibility of mice to coronary atherosclerosis development and progression to MI; 2)
Decipher the impact of Nogo-B-regulated ceramide and S1P signaling on MF biology and mechanistic
insights. This contribution is significant since will identify novel targets for the treatment of coronary
artery disease, 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 a relevant but understudied
metabolic pathway by using a novel mouse model of coronary atherosclerosis with progression to MI
that better recapitulates the human disease, a heretofore-unexamined process.