RFX1 regulates foam cell formation and atherosclerosis by mediating CD36 expression

Area of Science:

• Immunology
• Cardiovascular Research
• Molecular Biology

Background:

• Atherosclerosis (AS) is a chronic inflammatory disease where macrophages play a critical role.
• Regulatory factor X1 (RFX1) is involved in cell differentiation, with decreased expression observed in AS patients' monocytes.
• The specific function of RFX1 in macrophage-derived foam cell formation and AS pathogenesis remains unclear.

Purpose of the Study:

• To investigate the role of RFX1 in oxidized low-density lipoprotein (ox-LDL)-induced foam cell formation.
• To determine the effect of RFX1 on CD36 expression and its transcriptional regulation.
• To elucidate the impact of RFX1 deficiency on atherosclerosis development in vivo.

Main Methods:

• Manipulating RFX1 expression (upregulation/silencing) in mouse peritoneal macrophages (PMAs) exposed to ox-LDL.
• Utilizing ApoE-/-Rfx1f/f and ApoE-/-Rfx1f/f Lyz2-Cre mouse models fed a high-fat diet.
• Employing dual luciferase reporter assays to analyze RFX1's regulation of CD36 transcription.

Main Results:

• RFX1 expression is reduced in ox-LDL-induced foam cells and inversely correlates with lipid uptake in macrophages.
• RFX1 deficiency in myeloid cells exacerbates atherosclerotic lesions in ApoE-/- mice.
• RFX1 directly inhibits CD36 transcription, thereby reducing lipid accumulation in macrophages.

Conclusions:

• Reduced RFX1 expression in macrophages is a critical factor in foam cell formation and AS initiation.
• RFX1 acts as a suppressor of CD36 expression, modulating macrophage lipid metabolism.
• Targeting RFX1 presents a potential novel therapeutic strategy for treating atherosclerosis.