ArticleThe Journal of clinical investigation2021
Deficiency of macrophage PHACTR1 impairs efferocytosis and promotes atherosclerotic plaque necrosis.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 47 citations in OpenAlex.
- Review
- Integrative genetic analysis reveals shared genetic architecture underlying coronary artery disease, CT-Defined coronary atherosclerosis, and cardiometabolic risk factors.Functional & integrative genomics · 2026Article
- Molecular systems, human noncoding sequence variants, and blood pressure.Physiological reviews · 2026Review
- More Than a Cleanup Crew: The Expanding Biology of Efferocytosis.Arteriosclerosis, thrombosis, and vascular biology · 2026Review
- Proteomic and morphologic characterization of ovine macrophage differentiation and polarization.Scientific reports · 2025Article
- Activated protein C ameliorates diabetes-induced atherosclerosis by sustaining macrophage efferocytosis.Cardiovascular diabetology · 2025Article
- Trained immunity in atherosclerosis: plasticity, metabolic-vascular axis, and AI-driven precision remodeling.Frontiers in immunology · 2025Review
- Six genetic variants are associated with cardiovascular disease independently from canonical risk factors: a new method to refine GWAS results based on the UKBiobank phenotype database.Molecular genetics and genomics : MGG · 2024Article
- Efferocytosis in atherosclerosis.Nature reviews. Cardiology · 2024Review
- Article
- Mechanistic insights into the regression of atherosclerotic plaques.Frontiers in physiology · 2024Review
- Efferocytosis: the resolution of inflammation in cardiovascular and cerebrovascular disease.Frontiers in immunology · 2024Review
- Developmental endothelial locus 1: the present and future of an endogenous factor in vessels.Frontiers in physiology · 2024Review
- Efferocytosis-induced lactate enables the proliferation of pro-resolving macrophages to mediate tissue repair.Nature metabolism · 2023Article
- Construction and validation of an efferocytosis-related prognostic signature in lung adenocarcinoma.Journal of cancer research and clinical oncology · 2023Article
- Endothelial PHACTR1 Promotes Endothelial Activation and Atherosclerosis by Repressing PPARγ Activity Under Disturbed Flow in Mice.Arteriosclerosis, thrombosis, and vascular biology · 2023Article
- Network Preservation Analysis Reveals Dysregulated Metabolic Pathways in Human Vascular Smooth Muscle Cell Phenotypic Switching.Circulation. Genomic and precision medicine · 2023Article
- PHACTR1 and Atherosclerosis: It's Complicated.Arteriosclerosis, thrombosis, and vascular biology · 2023Article
- Exosomal Non-Coding RNA Mediates Macrophage Polarization: Roles in Cardiovascular Diseases.Biology · 2023Review
- PHACTR1 modulates vascular compliance but not endothelial function: a translational study.Cardiovascular research · 2023Article
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.