Abstract Body (Do not enter title and authors here): Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide, with atherosclerosis serving as a common cause of heart attacks and strokes. Elevated low-density lipoprotein-cholesterol (LDL-C) and oxidized LDL (oxLDL) represent two primary drivers of atherosclerosis and itsprogression. Nitric oxide (NO) reduces cardiovascular risk through combined effects on endothelial function, platelet aggregation, leukocyte adhesion, blood pressure, and diabetes; however, roles for NO in cholesterol metabolism and LDL oxidation remain largely unknown. NO-based signaling is conveyed in large part by protein S-nitrosylation, the post-translational modification of specific cysteine residues on proteins by NO, but mechanisms determining specificity of this regulatory modification are poorly defined. We identified a novel protein S-nitrosylation system centered on S-nitroso-Co-enzyme A (SNO-CoA) and two associated enzymes, SNO-CoA-assisted nitrosylase (SCAN) and SNO-CoA reductase (SCoR). SNO-CoA acts as cofactor for SCAN and as substrate for SCoR to place SNO on or remove SNO from target proteins, respectively. SCoR regulates the S-nitrosylation of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) and Pyruvate Kinase M2 (PKM2): PCSK9 increases serum LDL-C level by degrading LDL receptors on hepatocytes, while PKM2 is an isoenzyme of the glycolytic enzyme pyruvate kinase, and its inhibition reprograms metabolism from glycolysis into the pentose phosphate pathway that generates the vast majority of cellular NADPH to detoxify damaging reactive oxygen species. Mice with SCoR gene deletion demonstrate resistance to atherogenesis due to two key effects: 1) reduction in serum LDL-C levels mediated by hyper-S-nitrosylation of PCSK9; and 2) decrease in serum oxLDL levels mediated by hyper-S-nitrosylation of PKM2. Conversely, mice lacking SCAN exhibit elevated atherogenesis. This study provides the first insights into the role of the SCoR/SCAN system in atherosclerosis, mediated via S-nitrosylation of PCSK9 and PKM2, defining a novel role for NO in protection from atherosclerosis.