Plasminogen Deficiency Significantly Reduces Vascular Wall Disease in a Murine Model of Type IIa Hypercholesterolemia

Area of Science:

• Cardiovascular Biology
• Lipid Metabolism
• Thrombosis and Hemostasis

Background:

• The fibrinolytic system, including plasminogen (Pg), is implicated in atherosclerosis development.
• Previous studies suggest plasminogen deficiency exacerbates atherosclerosis in certain mouse models.
• The role of Pg in low-density lipoprotein-cholesterol (LDL-C)-driven atherosclerosis remains unclear.

Purpose of the Study:

• To investigate the specific role of plasminogen (Pg) in an LDL-C-driven atherosclerosis model.
• To characterize the impact of Pg on lipoprotein metabolism and clearance in the absence of LDL receptors.

Main Methods:

• Generation of triple-deficient mice lacking LDL-receptor (LDLr), apobec1, and plasminogen (Pg) (L/A/Plg).
• Assessment of atherosclerotic plaque formation in these mice.
• In vitro studies to evaluate LDL uptake by macrophages and circulating LDL levels.

Main Results:

• Atherosclerotic plaque formation was significantly reduced in mice lacking Pg.
• Plasmin (Pm) enhanced LDL uptake by macrophages in vitro.
• Circulating LDL levels were elevated, and VLDL synthesis was suppressed in L/A/Plg mice compared to L/A mice.

Conclusions:

• Plasminogen (Pg) promotes atherosclerosis in an LDL-C-driven model.
• Pg/plasmin system influences lipoprotein modification and clearance, particularly in LDLr-deficient conditions.
• Targeting the Pg system on macrophages presents a potential therapeutic strategy to prevent foam cell formation and mitigate atherosclerosis.