Angiotensin II deteriorates advanced atherosclerosis by promoting MerTK cleavage and impairing efferocytosis through the AT₁R/ROS/p38 MAPK/ADAM17 pathway

Abstract

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 (AT1R) blocker losartan suppressed ROS production, and ROS scavenger N-acetyl-l-cysteine (NAC) prevented p38 MAPK phosphorylation. In addition, mutant MERTKΔ483-488 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 AT1R/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.

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“…In addition, P38 was reported to be involved in the regulation of efferocytosis. Zhang et al found that angiotensin II damages efferocytosis in advanced atherosclerosis, which is involved in P38 pathway [62]. Recently, D Gilroy et al reported that inhibition of the elevated p38 MAPK could restore efferocytosis and enhance the inflammatory resolution in the elderly [63], indicating targeting P38 could be a potent strategy to modulate chronic inflammation via efferocytosis.…”

Different Approaches in Therapy Aiming to Stabilize an Unstable Atherosclerotic Plaque

“…(a) Promotion of macrophage autophagy [38]; (b) Efficient efferocytosis of apoptotic bodies [36]. Cytotoxic CD8 + T lymphocyte (Tc) depletion [100] CD8α or CD8β targeted monoclonal antibody Regulatory T lymphocyte (Treg) promotion [101].…”

“…For appropriate efferocytosis, a Mer Tyrosine Kinase (MerTK) expressed on the macrophage surface is required and pathways, which promote MerTK shedding from a membrane to the soluble form, impair this process. For instance, angiotensin II negatively affects efferocytosis through ADAM17 activation and subsequent MerTK shedding [ 38 ]. Apart from the aspects of cellular death, interventions preventing macrophage conversion into foam cells (such as inhibition of LOX-1, a receptor recognizing and internalizing oxLDL particles) as well as reverse cholesterol transport promotion in foam cells via LXRα receptor activation have been demonstrated to be atheroprotective in animal models [ 39 , 40 , 41 ].…”

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“…157 Ang II induces shedding of MerTK off the cell membrane through AT1R/ROS/p38MAPK/ADAM17 pathway. 158 Consequently, Ang II impairs switching M1 to M2. Continuation of pro-inflammatory status result in activation of MMPs and inducing of ECM remodeling processes.…”