PMID- 31390228 OWN - NLM STAT- MEDLINE DCOM- 20200408 LR - 20200930 IS - 1522-1563 (Electronic) IS - 0363-6143 (Linking) VI - 317 IP - 4 DP - 2019 Oct 1 TI - Angiotensin II deteriorates advanced atherosclerosis by promoting MerTK cleavage and impairing efferocytosis through the AT(1)R/ROS/p38 MAPK/ADAM17 pathway. PG - C776-C787 LID - 10.1152/ajpcell.00145.2019 [doi] AB - Vulnerable plaques in advanced atherosclerosis have defective efferocytosis. The role of ANG II in the progression of atherosclerosis is not fully understood. Herein, we investigated the effects and the underlying mechanisms of ANG II on macrophage efferocytosis in advanced atherosclerosis. ANG II decreased the surface expression of Mer tyrosine kinase (MerTK) in macrophages through a disintegrin and metalloproteinase17 (ADAM17)-mediated shedding of the soluble form of MerTK (sMer) in the medium, which led to efferocytosis suppression. ANG II-activated ADAM17 required reactive oxygen species (ROS) and p38 MAPK phosphorylation. Selective angiotensin II type 1 receptor (AT(1)R) blocker losartan suppressed ROS production, and ROS scavenger N-acetyl-l-cysteine (NAC) prevented p38 MAPK phosphorylation. In addition, mutant MERTK(Delta483-488) was resistant to ANG II-induced MerTK shedding and efferocytosis suppression. The advanced atherosclerosis model that is characterized by larger necrotic cores, and less collagen content was established by feeding apolipoprotein E knockout (ApoE(-/-)) mice with a high-fat diet for 16 wk. NAC and losartan oral administration prevented atherosclerotic lesion progression. Meanwhile, the inefficient efferocytosis represented by decreased macrophage-associated apoptotic cells and decreased MerTK(+)CD68(+)double-positive macrophages in advanced atherosclerosis were prevented by losartan and NAC. Additionally, the serum levels of sMer were increased and positively correlated with the upregulated levels of ANG II in acute coronary syndrome (ACS) patients. In conclusion, ANG II promotes MerTK shedding via AT(1)R/ROS/p38 MAPK/ADAM17 pathway in macrophages, which led to defective efferocytosis and atherosclerosis progression. Defining the molecular mechanisms of defective efferocytosis may provide a promising prognosis and therapy for ACS patients. FAU - Zhang, Yan AU - Zhang Y AD - Department of Cardiovascular Medicine, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China. FAU - Wang, Ying AU - Wang Y AD - Department of Critical Care Medicine, Xi'an No. 4 Hospital, Xi'an, China. FAU - Zhou, Dong AU - Zhou D AD - Department of Cardiovascular Medicine, Hanzhong 3201 Hospital, Hanzhong, China. FAU - Zhang, Li-Sha AU - Zhang LS AD - Department of Cardiovascular Medicine, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China. FAU - Deng, Fu-Xue AU - Deng FX AD - Department of Cardiovascular Medicine, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China. FAU - Shu, Shan AU - Shu S AD - Department of Cardiovascular Medicine, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China. FAU - Wang, Li-Jun AU - Wang LJ AD - Department of Cardiovascular Medicine, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China. FAU - Wu, Yue AU - Wu Y AD - Department of Cardiovascular Medicine, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China. FAU - Guo, Ning AU - Guo N AD - Department of Cardiovascular Medicine, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China. FAU - Zhou, Juan AU - Zhou J AD - Department of Cardiovascular Medicine, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China. AD - Key Laboratory of Molecular Cardiology of Shannxi Province, Xi'an, China. FAU - Yuan, Zu-Yi AU - Yuan ZY AD - Department of Cardiovascular Medicine, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China. AD - Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, China. AD - Key Laboratory of Molecular Cardiology of Shannxi Province, Xi'an, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190807 PL - United States TA - Am J Physiol Cell Physiol JT - American journal of physiology. Cell physiology JID - 100901225 RN - 0 (Reactive Oxygen Species) RN - 11128-99-7 (Angiotensin II) RN - EC 2.7.10.1 (Protein-Tyrosine Kinases) RN - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) RN - EC 2.7.10.1 (c-Mer Tyrosine Kinase) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - EC 3.4.24.86 (ADAM17 Protein) SB - IM MH - ADAM17 Protein/*drug effects MH - Angiotensin II/*pharmacology MH - Animals MH - Atherosclerosis/drug therapy/*metabolism MH - Humans MH - Macrophages/drug effects/metabolism MH - Mice, Transgenic MH - Phagocytosis/drug effects MH - Protein-Tyrosine Kinases/drug effects/metabolism MH - Reactive Oxygen Species/*metabolism MH - Receptor Protein-Tyrosine Kinases/drug effects/metabolism MH - c-Mer Tyrosine Kinase/*drug effects MH - p38 Mitogen-Activated Protein Kinases/drug effects/metabolism OTO - NOTNLM OT - ANG II OT - MerTK OT - atherosclerosis OT - efferocytosis OT - macrophage EDAT- 2019/08/08 06:00 MHDA- 2020/04/09 06:00 CRDT- 2019/08/08 06:00 PHST- 2019/08/08 06:00 [pubmed] PHST- 2020/04/09 06:00 [medline] PHST- 2019/08/08 06:00 [entrez] AID - 10.1152/ajpcell.00145.2019 [doi] PST - ppublish SO - Am J Physiol Cell Physiol. 2019 Oct 1;317(4):C776-C787. doi: 10.1152/ajpcell.00145.2019. Epub 2019 Aug 7.