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

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Redox Signaling

Background:

• Atherosclerosis (AS) is a major cause of cardiovascular diseases.
• S-nitrosylation (SNO) is a redox modification implicated in cardiovascular pathology.
• Macrophage lipid uptake and foam cell formation are key processes in AS development.

Purpose of the Study:

• To investigate the role of S-nitrosylation of Histidine triad nucleotide-binding protein 1 (HINT1) in atherosclerosis.
• To elucidate the molecular mechanisms by which SNO-HINT1 influences macrophage function and AS progression.
• To identify inducible nitric oxide synthase (iNOS) as the enzyme responsible for HINT1 S-nitrosylation.

Main Methods:

• Utilized oxidized low-density lipoprotein (ox-LDL) stimulated macrophages and LDLR-/- mice on a high-fat diet.
• Investigated S-nitrosylation of HINT1 at Cys84.
• Analyzed the impact of SNO-HINT1 on scavenger receptor A1 (SR-A1) and CD36 expression and localization.
• Examined the role of lysosomal degradation and USF2 transcription factor.

Main Results:

• S-nitrosylation of HINT1 (SNO-HINT1) in macrophages exacerbates lipid uptake and foam cell formation.
• SNO-HINT1 upregulates SR-A1 and CD36 expression by inhibiting SR-A1 lysosomal degradation and promoting CD36 transcription via USF2.
• SNO-HINT1 undergoes CRM1-dependent nuclear export, increasing cytoplasmic interaction with SR-A1 and reducing nuclear interaction with USF2.
• iNOS mediates HINT1 S-nitrosylation, and SNO-HINT1 promotes atherosclerosis in vivo.

Conclusions:

• SNO-HINT1 drives foam cell formation and atherosclerosis progression.
• The mechanism involves reduced lysosomal degradation of SR-A1 and enhanced CD36 transcription.
• SNO-HINT1 represents a potential therapeutic target for atherosclerosis.