Deficiency of macrophage PHACTR1 impairs efferocytosis and promotes atherosclerotic plaque necrosis
| العنوان: | Deficiency of macrophage PHACTR1 impairs efferocytosis and promotes atherosclerotic plaque necrosis |
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| المؤلفون: | Ze Zheng, Gabrielle Fredman, Chenyi Xue, Danish Saleheen, Xiaobo Wang, Hanrui Zhang, Bernhard Dorweiler, Brennan D. Gerlach, George Kuriakose, Muredach P. Reilly, Maaike Schilperoort, Ira Tabas, Canan Kasikara |
| المصدر: | J Clin Invest |
| بيانات النشر: | American Society for Clinical Investigation, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Myosin Light Chains, Myosin light-chain kinase, Necrosis, Apoptosis, Inflammation, Coronary Artery Disease, Jurkat Cells, Mice, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Humans, Macrophage, Gene silencing, Phosphorylation, Efferocytosis, Mice, Knockout, Polymorphism, Genetic, business.industry, Macrophages, Microfilament Proteins, General Medicine, Plaque, Atherosclerotic, Haematopoiesis, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer research, medicine.symptom, business, Research Article |
| الوصف: | 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. |
| تدمد: | 1558-8238 0021-9738 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fcdde2db6acbf17f23588ebea4a92da0 https://doi.org/10.1172/jci145275 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....fcdde2db6acbf17f23588ebea4a92da0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15588238 00219738 |
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