Macrophage Gene Expression and Foam Cell Formation is Regulated by Plasminogen
Background—Deciphering the molecular and cellular processes that govern macrophage foam cell formation is critical to understanding basic mechanisms underlying atherosclerosis and other vascular pathologies.
Methods and Results—Here, we identify a pivotal role of plasminogen in regulating foam cell formation. Deficiency of plasminogen inhibited macrophage cholesterol accumulation upon exposure to hyperlipidemic conditions in vitro, ex vivo and in vivo. Gene expression analysis identified CD36 as a regulated target of plasminogen, and macrophages from Plg-/- mice had decreased CD36 expression and diminished foam cell formation. The plasminogen-dependent CD36 expression and foam cell formation depended on conversion of plasminogen to plasmin, binding to the macrophage surface, and the consequent intracellular signaling that leads to production of leukotrieneB4. Leukotriene B4 rescued the suppression of CD36 expression and foam cell formation arising from plasminogen deficiency.
Conclusions—Our findings demonstrate an unanticipated role of plasminogen in regulation of gene expression and cholesterol metabolism by macrophages and identify plasminogen-mediated regulation of leukotrieneB4 as an underlying mechanism.
- Received January 9, 2013.
- Accepted January 14, 2013.
- Copyright © 2013, Circulation