Macrophage Apoptosis and Efferocytosis in the Pathogenesis of Atherosclerosis
| Autor: | Huan Tao, Edward F Linton, Vladimir R. Babaev, Jiansheng Huang, Patricia G. Yancey, MacRae F. Linton |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
AKT1 AKT2 Mechanistic Target of Rapamycin Complex 2 IκB kinase Article AKT3 03 medical and health sciences Animals Humans Medicine Macrophage Mitogen-Activated Protein Kinase 8 Efferocytosis Protein kinase B PI3K/AKT/mTOR pathway business.industry Macrophages TOR Serine-Threonine Kinases General Medicine Atherosclerosis Endoplasmic Reticulum Stress I-kappa B Kinase Cell biology Isoenzymes 030104 developmental biology Multiprotein Complexes Immunology Unfolded Protein Response Cardiology and Cardiovascular Medicine business Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Circulation Journal. 80:2259-2268 |
| ISSN: | 1347-4820 1346-9843 |
| Popis: | Macrophage apoptosis and the ability of macrophages to clean up dead cells, a process called efferocytosis, are crucial determinants of atherosclerosis lesion progression and plaque stability. Environmental stressors initiate endoplasmic reticulum (ER) stress and activate the unfolded protein response (UPR). Unresolved ER stress with activation of the UPR initiates apoptosis. Macrophages are resistant to apoptotic stimuli, because of activity of the PI3K/Akt pathway. Macrophages express 3 Akt isoforms, Akt1, Akt2 and Akt3, which are products of distinct but homologous genes. Akt displays isoform-specific effects on atherogenesis, which vary with different vascular cell types. Loss of macrophage Akt2 promotes the anti-inflammatory M2 phenotype and reduces atherosclerosis. However, Akt isoforms are redundant with regard to apoptosis. c-Jun NH2-terminal kinase (JNK) is a pro-apoptotic effector of the UPR, and the JNK1 isoform opposes anti-apoptotic Akt signaling. Loss of JNK1 in hematopoietic cells protects macrophages from apoptosis and accelerates early atherosclerosis. IκB kinase α (IKKα, a member of the serine/threonine protein kinase family) plays an important role in mTORC2-mediated Akt signaling in macrophages, and IKKα deficiency reduces macrophage survival and suppresses early atherosclerosis. Efferocytosis involves the interaction of receptors, bridging molecules, and apoptotic cell ligands. Scavenger receptor class B type I is a critical mediator of macrophage efferocytosis via the Src/PI3K/Rac1 pathway in atherosclerosis. Agonists that resolve inflammation offer promising therapeutic potential to promote efferocytosis and prevent atherosclerotic clinical events. (Circ J 2016; 80: 2259-2268). |
| Databáze: | OpenAIRE |
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