BACKGROUND: Deciphering the molecular and cellular processes that govern macrophage foam cell formation is critical to understanding the basic mechanisms underlying atherosclerosis and other vascular pathologies. METHODS AND RESULTS: Here, we identify a pivotal role of plasminogen (Plg) in regulating foam cell formation. Deficiency of Plg inhibited macrophage cholesterol accumulation on exposure to hyperlipidemic conditions in vitro, ex vivo, and in vivo. Gene expression analysis identified CD36 as a regulated target of Plg, and macrophages from Plg(-/-) mice had decreased CD36 expression and diminished foam cell formation. The Plg-dependent CD36 expression and foam cell formation depended on conversion of Plg to plasmin, binding to the macrophage surface, and the consequent intracellular signaling that leads to production of leukotriene B4. Leukotriene B4 rescued the suppression of CD36 expression and foam cell formation arising from Plg deficiency. CONCLUSIONS: Our findings demonstrate an unanticipated role of Plg in the regulation of gene expression and cholesterol metabolism by macrophages and identify Plg-mediated regulation of leukotriene B4 as an underlying mechanism.
BACKGROUND: Deciphering the molecular and cellular processes that govern macrophage foam cell formation is critical to understanding the basic mechanisms underlying atherosclerosis and other vascular pathologies. METHODS AND RESULTS: Here, we identify a pivotal role of plasminogen (Plg) in regulating foam cell formation. Deficiency of Plg inhibited macrophage cholesterol accumulation on exposure to hyperlipidemic conditions in vitro, ex vivo, and in vivo. Gene expression analysis identified CD36 as a regulated target of Plg, and macrophages from Plg(-/-) mice had decreased CD36 expression and diminished foam cell formation. The Plg-dependent CD36 expression and foam cell formation depended on conversion of Plg to plasmin, binding to the macrophage surface, and the consequent intracellular signaling that leads to production of leukotriene B4. Leukotriene B4 rescued the suppression of CD36 expression and foam cell formation arising from Plgdeficiency. CONCLUSIONS: Our findings demonstrate an unanticipated role of Plg in the regulation of gene expression and cholesterol metabolism by macrophages and identify Plg-mediated regulation of leukotriene B4 as an underlying mechanism.
Authors: M Febbraio; E A Podrez; J D Smith; D P Hajjar; S L Hazen; H F Hoff; K Sharma; R L Silverstein Journal: J Clin Invest Date: 2000-04 Impact factor: 14.808
Authors: E A Podrez; M Febbraio; N Sheibani; D Schmitt; R L Silverstein; D P Hajjar; P A Cohen; W A Frazier; H F Hoff; S L Hazen Journal: J Clin Invest Date: 2000-04 Impact factor: 14.808
Authors: Qianyi Ma; Ayse B Ozel; Shweta Ramdas; Beth McGee; Rami Khoriaty; David Siemieniak; Hong-Dong Li; Yuanfang Guan; Lawrence C Brody; James L Mills; Anne M Molloy; David Ginsburg; Jun Z Li; Karl C Desch Journal: Blood Date: 2014-09-10 Impact factor: 22.113
Authors: Jie Hong Hu; Phanith Touch; Jingwan Zhang; Hao Wei; Shihui Liu; Ida K Lund; Gunilla Høyer-Hansen; David A Dichek Journal: Cardiovasc Res Date: 2015-01-23 Impact factor: 10.787
Authors: Kai Yin; Yong You; Vicki Swier; Lin Tang; Mohamed M Radwan; Amit N Pandya; Devendra K Agrawal Journal: Arterioscler Thromb Vasc Biol Date: 2015-09-17 Impact factor: 8.311