Plasminogen promotes cholesterol efflux by the ABCA1 pathway

Area of Science:

• Biochemistry
• Genetics
• Cardiovascular Disease Research

Background:

• Macrophage cholesterol efflux capacity (CEC) and ABCA1-specific CEC (ABCA1 CEC) are functional assays predicting cardiovascular disease (CVD).
• Reduced CEC is linked to increased CVD risk, highlighting the need to understand its regulatory proteins.

Purpose of the Study:

• To investigate proteins regulating macrophage CEC and ABCA1 CEC.
• To identify key determinants of cholesterol efflux and their potential role in CVD.

Main Methods:

• Genetic and biochemical approaches in mouse models.
• High-resolution size-exclusion and ion-exchange chromatography.
• Shotgun proteomics and functional cholesterol efflux assays.

Main Results:

• Apolipoprotein A-I (APOA1) and apolipoprotein E (APOE) deficiency reduced overall CEC, while only APOA1 deficiency significantly impacted ABCA1 CEC.
• Plasminogen (PLG) was identified as a major contributor to ABCA1 CEC in a non-HDL associated fraction.
• Human PLG promoted ABCA1-mediated cholesterol efflux, an effect inhibited by lipoprotein(a) [Lp(a)].

Conclusions:

• APOA1, APOE, and PLG are identified as critical regulators of macrophage CEC.
• The interaction between PLG and Lp(a) may influence CVD pathogenesis by modulating cholesterol efflux.