Abstract 028: Endothelial Nogo-B Controls Sphingolipid de novo Biosynthesis to Impact Coronary Artery Atherosclerosis

Coronary artery disease is a leading cause of myocardial infarction (MI) worldwide. Alterations in sphingolipid levels have been linked to atherosclerosis although specific molecular mechanisms are poorly understood. Recently, we discovered that endothelial Nogo-B, a membrane protein of the ER, regulates vascular functions by inhibiting serine palmitoyltransferase (SPT), the rate-limiting enzyme of the de novo sphingolipid biosynthesis. Mice lacking Nogo-B are resistant to hypertension and heart failure. Here, we employed a novel model of coronary atherosclerotic lesions induced by hypercholesterolemia and hypertension, well-known risk factors for atherosclerosis. To this aim, transverse aortic constriction (TAC) surgery was performed in mice lacking endothelial Nogo-B in ApoE -/- background and ApoE -/- mice as control. ApoE -/- mice developed coronary atherosclerotic lesions within 6 weeks following TAC, (without the need of long-term high-cholesterol diet) and 70% of the mice died of MI at 6-week post-TAC. On the contrary, mice lacking Nogo-B specifically in endothelial cells were markedly resistant to the development of coronary atherosclerotic lesions and MI (20%). Mechanistically, in the absence of endothelial Nogo-B, the biosynthesis of sphingolipids, particularly S1P, is upregulated, protecting the endothelium from hypertension and hypercholesterolemia-triggered vascular inflammation and atherogenesis. This study identifies an important and novel role of endothelial Nogo-B-dependent regulation of sphingolipid de novo biosynthesis in the coronary atherosclerosis, a primary cause of myocardial infarction.