S-nitrosylation of HINT1 in macrophages aggravates foam cell formation and atherosclerosis.

Atherosclerosis (AS) is the primary cause of most cardiovascular diseases, such as coronary artery disease (CAD), myocardial infarctions and strokes. S-nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in cardiovascular diseases. Histidine triad nucleotide-binding protein 1 (HINT1) was identified S-nitrosylated at cysteine 84 (Cys84) in oxidized low-density lipoprotein (ox-LDL)-stimulated macrophages. S-nitrosylation of HINT1 (SNO-HINT1) in macrophages exacerbates lipid uptake and foam cell formation through upregulating SR-A1 and CD36. Furthermore, SNO-HINT1 was determined to inhibit degradation of SR-A1 mediated by lysosome pathway and promote CD36 transcription mediated by USF2. Mechanistically, comparing to unmodified HINT1, S-nitrosylation of HINT1 drives its CRM1 dependent nuclear export, which resulted in its more interaction with SR-A1 in cytoplasm and less interaction with USF2 in nucleus. Furthermore, inducible nitric oxide synthase (iNOS) was demonstrated as the enzyme that mediates the S-nitrosylation of HINT1. SNO-HINT1 was demonstrated to drive the development of atherosclerosis in LDLR(-/-) mice fed with high fat diet. Overall, SNO-HINT1 drives foam cell formation and atherosclerosis through reducing degradation of SR-A1 mediated by lysosome pathway and promoting CD36 transcription mediated by USF2. Our findings suggest that SNO-HINT1 can be a potential therapeutic target for atherosclerosis.