Oxidized Low‐Density Lipoprotein Induces Macrophage Production of Prothrombotic Microparticles
Background Activated vascular cells produce submicron prothrombotic and proinflammatory microparticle vesicles. Atherosclerotic plaques contain high levels of microparticles. Plasma microparticle levels increase during acute coronary syndromes and the thrombotic consequences of plaque rupture likely...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2020-08-01
|
| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.120.015878 |
| _version_ | 1811332386363801600 |
|---|---|
| author | Julio F. Marchini Andre Manica Paulo Crestani Jochen Dutzmann Eduardo J. Folco Heinz Weber Peter Libby Kevin Croce |
| author_facet | Julio F. Marchini Andre Manica Paulo Crestani Jochen Dutzmann Eduardo J. Folco Heinz Weber Peter Libby Kevin Croce |
| author_sort | Julio F. Marchini |
| collection | DOAJ |
| description | Background Activated vascular cells produce submicron prothrombotic and proinflammatory microparticle vesicles. Atherosclerotic plaques contain high levels of microparticles. Plasma microparticle levels increase during acute coronary syndromes and the thrombotic consequences of plaque rupture likely involve macrophage‐derived microparticles (MΦMPs). The activation pathways that promote MΦMP production remain poorly defined. This study tested the hypothesis that signals implicated in atherogenesis also stimulate MΦMP production. Methods and Results We stimulated human primary MΦs with proinflammatory cytokines and atherogenic lipids, and measured MΦMP production by flow cytometry. Oxidized low‐density lipoprotein (oxLDL; 25 µg/mL) induced MΦMP production in a concentration‐dependent manner (293% increase; P<0.001), and these oxLDL MΦMP stimulatory effects were mediated by CD36. OxLDL stimulation increased MΦMP tissue factor content by 78% (P<0.05), and oxLDL‐induced MΦMP production correlated with activation of caspase 3/7 signaling pathways. Salvionolic acid B, a CD36 inhibitor and a CD36 inhibitor antibody reduced oxLDL‐induced MΦMP by 67% and 60%, respectively. Caspase 3/7 inhibition reduced MΦMP release by 52% (P<0.01) and caspase 3/7 activation increased MΦMP production by 208% (P<0.01). Mevastatin pretreatment (10 µM) decreased oxLDL‐induced caspase 3/7 activation and attenuated oxLDL‐stimulated MΦMP production and tissue factor content by 60% (P<0.01) and 43% (P<0.05), respectively. Conclusions OxLDL induces the production of prothrombotic microparticles in macrophages. This process depends on caspases 3 and 7 and CD36 and is inhibited by mevastatin pretreatment. These findings link atherogenic signaling pathways, inflammation, and plaque thrombogenicity and identify a novel potential mechanism for antithrombotic effects of statins independent of LDL lowering. |
| first_indexed | 2024-04-13T16:35:59Z |
| format | Article |
| id | doaj.art-4a590055fb914cb69c7c7430383fe038 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-13T16:35:59Z |
| publishDate | 2020-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-4a590055fb914cb69c7c7430383fe0382022-12-22T02:39:25ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802020-08-0191510.1161/JAHA.120.015878Oxidized Low‐Density Lipoprotein Induces Macrophage Production of Prothrombotic MicroparticlesJulio F. Marchini0Andre Manica1Paulo Crestani2Jochen Dutzmann3Eduardo J. Folco4Heinz Weber5Peter Libby6Kevin Croce7Cardiovascular Division Department of Medicine Brigham and Women’s HospitalHarvard Medical School Boston MACardiovascular Division Department of Medicine Brigham and Women’s HospitalHarvard Medical School Boston MACardiovascular Division Department of Medicine Brigham and Women’s HospitalHarvard Medical School Boston MACardiovascular Division Department of Medicine Brigham and Women’s HospitalHarvard Medical School Boston MACardiovascular Division Department of Medicine Brigham and Women’s HospitalHarvard Medical School Boston MACardiovascular Division Department of Medicine Brigham and Women’s HospitalHarvard Medical School Boston MACardiovascular Division Department of Medicine Brigham and Women’s HospitalHarvard Medical School Boston MACardiovascular Division Department of Medicine Brigham and Women’s HospitalHarvard Medical School Boston MABackground Activated vascular cells produce submicron prothrombotic and proinflammatory microparticle vesicles. Atherosclerotic plaques contain high levels of microparticles. Plasma microparticle levels increase during acute coronary syndromes and the thrombotic consequences of plaque rupture likely involve macrophage‐derived microparticles (MΦMPs). The activation pathways that promote MΦMP production remain poorly defined. This study tested the hypothesis that signals implicated in atherogenesis also stimulate MΦMP production. Methods and Results We stimulated human primary MΦs with proinflammatory cytokines and atherogenic lipids, and measured MΦMP production by flow cytometry. Oxidized low‐density lipoprotein (oxLDL; 25 µg/mL) induced MΦMP production in a concentration‐dependent manner (293% increase; P<0.001), and these oxLDL MΦMP stimulatory effects were mediated by CD36. OxLDL stimulation increased MΦMP tissue factor content by 78% (P<0.05), and oxLDL‐induced MΦMP production correlated with activation of caspase 3/7 signaling pathways. Salvionolic acid B, a CD36 inhibitor and a CD36 inhibitor antibody reduced oxLDL‐induced MΦMP by 67% and 60%, respectively. Caspase 3/7 inhibition reduced MΦMP release by 52% (P<0.01) and caspase 3/7 activation increased MΦMP production by 208% (P<0.01). Mevastatin pretreatment (10 µM) decreased oxLDL‐induced caspase 3/7 activation and attenuated oxLDL‐stimulated MΦMP production and tissue factor content by 60% (P<0.01) and 43% (P<0.05), respectively. Conclusions OxLDL induces the production of prothrombotic microparticles in macrophages. This process depends on caspases 3 and 7 and CD36 and is inhibited by mevastatin pretreatment. These findings link atherogenic signaling pathways, inflammation, and plaque thrombogenicity and identify a novel potential mechanism for antithrombotic effects of statins independent of LDL lowering.https://www.ahajournals.org/doi/10.1161/JAHA.120.015878caspaselipidsmicroparticlesoxidizedsignal transductiontissue factor |
| spellingShingle | Julio F. Marchini Andre Manica Paulo Crestani Jochen Dutzmann Eduardo J. Folco Heinz Weber Peter Libby Kevin Croce Oxidized Low‐Density Lipoprotein Induces Macrophage Production of Prothrombotic Microparticles Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease caspase lipids microparticles oxidized signal transduction tissue factor |
| title | Oxidized Low‐Density Lipoprotein Induces Macrophage Production of Prothrombotic Microparticles |
| title_full | Oxidized Low‐Density Lipoprotein Induces Macrophage Production of Prothrombotic Microparticles |
| title_fullStr | Oxidized Low‐Density Lipoprotein Induces Macrophage Production of Prothrombotic Microparticles |
| title_full_unstemmed | Oxidized Low‐Density Lipoprotein Induces Macrophage Production of Prothrombotic Microparticles |
| title_short | Oxidized Low‐Density Lipoprotein Induces Macrophage Production of Prothrombotic Microparticles |
| title_sort | oxidized low density lipoprotein induces macrophage production of prothrombotic microparticles |
| topic | caspase lipids microparticles oxidized signal transduction tissue factor |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.120.015878 |
| work_keys_str_mv | AT juliofmarchini oxidizedlowdensitylipoproteininducesmacrophageproductionofprothromboticmicroparticles AT andremanica oxidizedlowdensitylipoproteininducesmacrophageproductionofprothromboticmicroparticles AT paulocrestani oxidizedlowdensitylipoproteininducesmacrophageproductionofprothromboticmicroparticles AT jochendutzmann oxidizedlowdensitylipoproteininducesmacrophageproductionofprothromboticmicroparticles AT eduardojfolco oxidizedlowdensitylipoproteininducesmacrophageproductionofprothromboticmicroparticles AT heinzweber oxidizedlowdensitylipoproteininducesmacrophageproductionofprothromboticmicroparticles AT peterlibby oxidizedlowdensitylipoproteininducesmacrophageproductionofprothromboticmicroparticles AT kevincroce oxidizedlowdensitylipoproteininducesmacrophageproductionofprothromboticmicroparticles |