SMC-specific IGF1 suppresses a 45 kDa LAMP2 isoform to mediate the anti-atherosclerotic effect of ferulic acid.

BACKGROUND AND AIMS: Ferulic acid (FA) exerts anti-atherosclerotic effects, but the underlying mechanisms remain incompletely understood. The present study investigated whether smooth muscle cell (SMC)-derived insulin-like growth factor 1 (IGF1) mediate FA's protective effects by regulating lysosome-associated membrane protein 2 (LAMP2), inflammatory cytokines, and matrix metalloproteinase 3 (MMP3). METHODS: Male ApoE-/- mice were fed a high-fat diet for 8 weeks to established atherosclerosis models and then treated with FA (40 mg/kg/d). SMC-specific Igf1 knockout (SMC-Igf1-KO) mice were generated to determine cell-type-specific requirements. In vitro, SMC-derived foam cells were induced by oxidized low-density lipoprotein (ox-LDL) and treated with FA ± IGF1 receptor (IGF1R) inhibitor. Plaque area, lipid deposition, and expression of IGF1, LAMP2, interleukin (IL)-6, IL-4, and MMP3 were assessed by en face staining, histology, Western blot, quantitative real-time PCR (qRT-PCR), and immunofluorescence selected as needed. RESULTS: FA treatment significantly reduced atherosclerotic plaque area and lipid deposition in male ApoE-/- mice, accompanied by upregulated IGF1 and downregulated 45 kDa-LAMP2 expression in aortic lesions. FA also increased IL-4 expression and decreased IL-6 and MMP3 expression. SMC-IGF1-KO significantly weakened the protective effects of FA. In vitro, FA increased IGF1 expression and IGF1R phosphorylation, reduced 45 kDa-LAMP2, IL-6, and MMP3 expression, and increased IL-4 expression in ox-LDL-induced SMC-derived foam cells. These effects were reversed by IGF1R inhibition. CONCLUSION: FA treatment significantly attenuates atherosclerosis. It partly resulted from that SMC-derived IGF1-mediated suppression of a 45 kDa-LAMP2 isoform, along with modulation of inflammatory balance (IL-6/IL-4) and MMP3 expression. The SMC-IGF1/45 kDa-LAMP2 axis may represent a potential therapeutic target for atherosclerosis.