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 M? 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 M? 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.
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 how alteration of a class of lipids, called sphingolipids, impact the development and progression of coronary atherosclerosis, providing a framework for target and drug discovery directed to ameliorate vascular inflammation in CAD and other CV conditions.
