Functional Crosstalk between PCSK9 Internalization and Pro-Inflammatory Activation in Human Macrophages: Role of Reactive Oxygen Species Release
Atherosclerosis is a cardiovascular disease caused mainly by dyslipidemia and is characterized by the formation of an atheroma plaque and chronic inflammation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease that induces the degradation of the LDL receptor (LDLR), which contribut...
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MDPI AG
2022-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/16/9114 |
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| author | Rafael I. Jaén Adrián Povo-Retana César Rosales-Mendoza Patricia Capillas-Herrero Sergio Sánchez-García Paloma Martín-Sanz Marina Mojena Patricia Prieto Lisardo Boscá |
| author_facet | Rafael I. Jaén Adrián Povo-Retana César Rosales-Mendoza Patricia Capillas-Herrero Sergio Sánchez-García Paloma Martín-Sanz Marina Mojena Patricia Prieto Lisardo Boscá |
| author_sort | Rafael I. Jaén |
| collection | DOAJ |
| description | Atherosclerosis is a cardiovascular disease caused mainly by dyslipidemia and is characterized by the formation of an atheroma plaque and chronic inflammation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease that induces the degradation of the LDL receptor (LDLR), which contributes to increased levels of LDL cholesterol and the progress of atherosclerosis. Given that macrophages are relevant components of the lipidic and inflammatory environment of atherosclerosis, we studied the effects of PCSK9 treatment on human macrophages. Our data show that human macrophages do not express PCSK9 but rapidly incorporate the circulating protein through the LDLR and also activate the pro-inflammatory TLR4 pathway. Both LDLR and TLR4 are internalized after incubation of macrophages with exogenous PCSK9. PCSK9 uptake increases the production of reactive oxygen species and reduces the expression of genes involved in lipid metabolism and cholesterol efflux, while enhancing the production of pro-inflammatory cytokines through a TLR4-dependent mechanism. Under these conditions, the viability of macrophages is compromised, leading to increased cell death. These results provide novel insights into the role of PCSK9 in the crosstalk of lipids and cholesterol metabolism through the LDLR and on the pro-inflammatory activation of macrophages through TLR4 signaling. These pathways are relevant in the outcome of atherosclerosis and highlight the relevance of PCSK9 as a therapeutic target for the treatment of cardiovascular diseases. |
| first_indexed | 2024-03-09T04:20:29Z |
| format | Article |
| id | doaj.art-e9300524850a41bcbcd570b2b39f88e7 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T04:20:29Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-e9300524850a41bcbcd570b2b39f88e72023-12-03T13:48:30ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-08-012316911410.3390/ijms23169114Functional Crosstalk between PCSK9 Internalization and Pro-Inflammatory Activation in Human Macrophages: Role of Reactive Oxygen Species ReleaseRafael I. Jaén0Adrián Povo-Retana1César Rosales-Mendoza2Patricia Capillas-Herrero3Sergio Sánchez-García4Paloma Martín-Sanz5Marina Mojena6Patricia Prieto7Lisardo Boscá8Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, SpainInstituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, SpainInstituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, SpainInstituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, SpainInstituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, SpainInstituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, SpainInstituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, SpainDepartamento de Farmacología, Farmacognosia y Botánica, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, SpainInstituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, SpainAtherosclerosis is a cardiovascular disease caused mainly by dyslipidemia and is characterized by the formation of an atheroma plaque and chronic inflammation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease that induces the degradation of the LDL receptor (LDLR), which contributes to increased levels of LDL cholesterol and the progress of atherosclerosis. Given that macrophages are relevant components of the lipidic and inflammatory environment of atherosclerosis, we studied the effects of PCSK9 treatment on human macrophages. Our data show that human macrophages do not express PCSK9 but rapidly incorporate the circulating protein through the LDLR and also activate the pro-inflammatory TLR4 pathway. Both LDLR and TLR4 are internalized after incubation of macrophages with exogenous PCSK9. PCSK9 uptake increases the production of reactive oxygen species and reduces the expression of genes involved in lipid metabolism and cholesterol efflux, while enhancing the production of pro-inflammatory cytokines through a TLR4-dependent mechanism. Under these conditions, the viability of macrophages is compromised, leading to increased cell death. These results provide novel insights into the role of PCSK9 in the crosstalk of lipids and cholesterol metabolism through the LDLR and on the pro-inflammatory activation of macrophages through TLR4 signaling. These pathways are relevant in the outcome of atherosclerosis and highlight the relevance of PCSK9 as a therapeutic target for the treatment of cardiovascular diseases.https://www.mdpi.com/1422-0067/23/16/9114PCSK9LDLROSatherosclerosismacrophagecholesterol |
| spellingShingle | Rafael I. Jaén Adrián Povo-Retana César Rosales-Mendoza Patricia Capillas-Herrero Sergio Sánchez-García Paloma Martín-Sanz Marina Mojena Patricia Prieto Lisardo Boscá Functional Crosstalk between PCSK9 Internalization and Pro-Inflammatory Activation in Human Macrophages: Role of Reactive Oxygen Species Release International Journal of Molecular Sciences PCSK9 LDL ROS atherosclerosis macrophage cholesterol |
| title | Functional Crosstalk between PCSK9 Internalization and Pro-Inflammatory Activation in Human Macrophages: Role of Reactive Oxygen Species Release |
| title_full | Functional Crosstalk between PCSK9 Internalization and Pro-Inflammatory Activation in Human Macrophages: Role of Reactive Oxygen Species Release |
| title_fullStr | Functional Crosstalk between PCSK9 Internalization and Pro-Inflammatory Activation in Human Macrophages: Role of Reactive Oxygen Species Release |
| title_full_unstemmed | Functional Crosstalk between PCSK9 Internalization and Pro-Inflammatory Activation in Human Macrophages: Role of Reactive Oxygen Species Release |
| title_short | Functional Crosstalk between PCSK9 Internalization and Pro-Inflammatory Activation in Human Macrophages: Role of Reactive Oxygen Species Release |
| title_sort | functional crosstalk between pcsk9 internalization and pro inflammatory activation in human macrophages role of reactive oxygen species release |
| topic | PCSK9 LDL ROS atherosclerosis macrophage cholesterol |
| url | https://www.mdpi.com/1422-0067/23/16/9114 |
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