Sfrp5 protects acute myocardial infarction by inhibiting macrophage foam cell formation and apoptosis via modulation of macrophage polarization and p38-MAPK/JNK/NF-κB pathways.

AIMS: To investigate the role of secreted frizzled-related protein 5 (Sfrp5) in ST-segment elevation myocardial infarction (STEMI) and its protective mechanisms in macrophage-driven plaque instability.

MATERIALS AND

METHODS

Serum Sfrp5 levels were measured in 89 STEMI and 65 stable angina pectoris (SAP) patients. Foam macrophage models were established using murine RAW264.7 and human THP-1-derived macrophages. Sfrp5 effects on foam cell formation, apoptosis, and M1/M2 polarization were assessed, along with p38-MAPK/JNK/NF-κB signaling modulation using specific activators/inhibitors and RNA sequencing.

KEY FINDINGS: STEMI patients showed significantly lower serum Sfrp5 levels (P < 0.0001), negatively correlated with peak troponin T (P = 0.013). Sfrp5 suppressed foam cell formation, apoptosis, and M1 polarization while promoting M2 polarization in vitro. Inhibition of M2 polarization attenuated these effects. Mechanistically, Sfrp5 exerted protection by suppressing the p38-MAPK/JNK/NF-κB signaling axis, confirmed by RNA sequencing showing altered expression of genes involved in lipid metabolism, inflammation, and apoptosis.

SIGNIFICANCE: Sfrp5 enhances atherosclerotic plaque stability by inhibiting macrophage foam cell formation and apoptosis via suppression of p38-MAPK/JNK/NF-κB signaling and modulation of macrophage polarization, representing a potential therapeutic target for STEMI.