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Targeted invalidation of SR-B1 in macrophages reduces macrophage apoptosis and accelerates atherosclerosis.
- Source :
-
Cardiovascular research [Cardiovasc Res] 2020 Mar 01; Vol. 116 (3), pp. 554-565. - Publication Year :
- 2020
-
Abstract
- Aims: SR-B1 is a cholesterol transporter that exerts anti-atherogenic properties in liver and peripheral tissues in mice. Bone marrow (BM) transfer studies suggested an atheroprotective role in cells of haematopoietic origin. Here, we addressed the specific contribution of SR-B1 in the monocyte/macrophage.<br />Methods and Results: We generated mice deficient for SR-B1 in monocytes/macrophages (Lysm-Cre × SR-B1f/f) and transplanted their BM into Ldlr-/- mice. Fed a cholesterol-rich diet, these mice displayed accelerated aortic atherosclerosis characterized by larger macrophage-rich areas and decreased macrophage apoptosis compared with SR-B1f/f transplanted controls. These findings were reproduced in BM transfer studies using another atherogenic mouse recipient (SR-B1 KOliver × Cholesteryl Ester Transfer Protein). Haematopoietic reconstitution with SR-B1-/- BM conducted in parallel generated similar results to those obtained with Lysm-Cre × SR-B1f/f BM; thus suggesting that among haematopoietic-derived cells, SR-B1 exerts its atheroprotective role primarily in monocytes/macrophages. Consistent with our in vivo data, free cholesterol (FC)-induced apoptosis of macrophages was diminished in the absence of SR-B1. This effect could not be attributed to differential cellular cholesterol loading. However, we observed that expression of apoptosis inhibitor of macrophage (AIM) was induced in SR-B1-deficient macrophages, and notably upon FC-loading. Furthermore, we demonstrated that macrophages were protected from FC-induced apoptosis by AIM. Finally, AIM protein was found more present within the macrophage-rich area of the atherosclerotic lesions of SR-B1-deficient macrophages than controls.<br />Conclusion: Our findings suggest that macrophage SR-B1 plays a role in plaque growth by controlling macrophage apoptosis in an AIM-dependent manner.<br /> (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Animals
Aorta pathology
Aortic Diseases genetics
Aortic Diseases pathology
Apoptosis Regulatory Proteins metabolism
Atherosclerosis genetics
Atherosclerosis pathology
Bone Marrow Transplantation
Cholesterol metabolism
Disease Models, Animal
Disease Progression
Humans
Macrophages pathology
Macrophages transplantation
Mice, Inbred C57BL
Mice, Knockout
Receptors, LDL deficiency
Receptors, LDL genetics
Receptors, Scavenger metabolism
STAT3 Transcription Factor metabolism
Scavenger Receptors, Class B genetics
Signal Transduction
THP-1 Cells
Aorta metabolism
Aortic Diseases metabolism
Apoptosis
Atherosclerosis metabolism
Macrophages metabolism
Plaque, Atherosclerotic
Scavenger Receptors, Class B deficiency
Subjects
Details
- Language :
- English
- ISSN :
- 1755-3245
- Volume :
- 116
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 31119270
- Full Text :
- https://doi.org/10.1093/cvr/cvz138