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Deficiency of macrophage PHACTR1 impairs efferocytosis and promotes atherosclerotic plaque necrosis.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2021 Apr 15; Vol. 131 (8). - Publication Year :
- 2021
-
Abstract
- Efferocytosis, the process through which apoptotic cells (ACs) are cleared through actin-mediated engulfment by macrophages, prevents secondary necrosis, suppresses inflammation, and promotes resolution. Impaired efferocytosis drives the formation of clinically dangerous necrotic atherosclerotic plaques, the underlying etiology of coronary artery disease (CAD). An intron of the gene encoding PHACTR1 contains rs9349379 (A>G), a common variant associated with CAD. As PHACTR1 is an actin-binding protein, we reasoned that if the rs9349379 risk allele G causes lower PHACTR1 expression in macrophages, it might link the risk allele to CAD via impaired efferocytosis. We show here that rs9349379-G/G was associated with lower levels of PHACTR1 and impaired efferocytosis in human monocyte-derived macrophages and human atherosclerotic lesional macrophages compared with rs9349379-A/A. Silencing PHACTR1 in human and mouse macrophages compromised AC engulfment, and Western diet-fed Ldlr-/- mice in which hematopoietic Phactr1 was genetically targeted showed impaired lesional efferocytosis, increased plaque necrosis, and thinner fibrous caps - all signs of vulnerable plaques in humans. Mechanistically, PHACTR1 prevented dephosphorylation of myosin light chain (MLC), which was necessary for AC engulfment. In summary, rs9349379-G lowered PHACTR1, which, by lowering phospho-MLC, compromised efferocytosis. Thus, rs9349379-G may contribute to CAD risk, at least in part, by impairing atherosclerotic lesional macrophage efferocytosis.
- Subjects :
- Animals
Humans
Jurkat Cells
Mice
Mice, Knockout
Microfilament Proteins metabolism
Myosin Light Chains genetics
Myosin Light Chains metabolism
Phosphorylation genetics
Apoptosis
Coronary Artery Disease genetics
Coronary Artery Disease metabolism
Coronary Artery Disease pathology
Macrophages metabolism
Macrophages pathology
Microfilament Proteins deficiency
Plaque, Atherosclerotic genetics
Plaque, Atherosclerotic metabolism
Plaque, Atherosclerotic pathology
Polymorphism, Genetic
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 131
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 33630758
- Full Text :
- https://doi.org/10.1172/JCI145275