Back to Search
Start Over
Urokinase-type plasminogen activator (uPA) modulates monocyte-to-macrophage differentiation and prevents Ox-LDL-induced macrophage apoptosis
- Source :
- Atherosclerosis. 231:29-38
- Publication Year :
- 2013
- Publisher :
- Elsevier BV, 2013.
-
Abstract
- Objective Monocyte-to-macrophage differentiation and macrophage death play a pivotal role in atherogenesis. uPA and its receptor uPAR are expressed in atherosclerotic lesion macrophages and contribute to atherosclerosis progression. In the present study we investigated the effect and mechanisms of action of uPA on monocyte-to-macrophage differentiation and on macrophage apoptotic death. Methods and results The number of mouse peritoneal macrophages (MPM) harvested from uPAR-deficient (uPAR −/− ) mice was significantly lower by 30% in comparison to control C57BL/6 mice. In vitro, uPA intensified PMA-induced THP-1 monocyte differentiation, as determined by increased expression of the macrophage marker CD36. This effect was mediated via G1 arrest, downregulation of G2/S phase and inhibition of PMA-induced cell death. uPA attenuated MonoMac6 (MM6) macrophage-like cell line apoptosis induced by oxidized LDL (Ox-LDL) and by thapsigargin (inhibitor of sarco-endoplasmic reticulum Ca 2+ -ATPase), but not by staurosporine (protein kinase inhibitor), suggesting that uPA antiapoptotic activity is Ca 2+ -independent, but involves a kinase activation. The antiapoptotic activity of uPA was dependent on the presence of uPAR, and it involved ERK1/2 activation-dependent downregulation of the proapoptotic protein Bim in macrophages stimulated with Ox-LDL. Conclusions The present study demonstrates, for the first time, that uPA stimulates the differentiation of monocytes into macrophages and attenuates Ox-LDL-induced macrophage apoptotic death via ERK1/2 activation-dependent Bim downregulation. These processes may result in prolonged macrophage survival in the lesion, increased lesion cellularity, and eventually necrosis, which accelerates lesion development.
- Subjects :
- Male
Programmed cell death
CD36
Apoptosis
Biology
Monocytes
Mice
Downregulation and upregulation
Cell Line, Tumor
medicine
Animals
Humans
Macrophage
Extracellular Signal-Regulated MAP Kinases
Mice, Knockout
Macrophages
Monocyte
Cell Differentiation
Endoplasmic Reticulum Stress
Urokinase-Type Plasminogen Activator
Cell biology
Lipoproteins, LDL
Urokinase receptor
medicine.anatomical_structure
Monocyte differentiation
Macrophages, Peritoneal
biology.protein
Tetradecanoylphorbol Acetate
Cardiology and Cardiovascular Medicine
Subjects
Details
- ISSN :
- 00219150
- Volume :
- 231
- Database :
- OpenAIRE
- Journal :
- Atherosclerosis
- Accession number :
- edsair.doi.dedup.....8884f697d242420fe649a2fbbe242858