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2‐AAA Impairs Macrophage Efferocytosis and May Regulate the Development of Atherosclerosis
Author(s) -
Wang Chuan,
Doran Amanda C,
Ferguson Jane
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.03154
Subject(s) - efferocytosis , macrophage , inflammation , medicine , disease , immunology , biology , biochemistry , in vitro
Cardiometabolic disease, including cardiovascular disease (CVD) and type 2 diabetes (T2D), is the leading cause of mortality in the US. In many cases, the underlying causes of disease are not known, and there is an urgent need to better understand the mechanisms underlying disease development. The amino acid‐derived metabolite alpha‐aminoadipic acid (2‐AAA) has been identified as a biomarker of T2D and atherosclerosis through metabolomic profiling in epidemiological cohorts. While very little is known about 2‐AAA function, we and others have identified relationships between the 2‐AAA pathway and mitochondrial dysfunction. Efferocytosis, a macrophage‐mediated process for clearance of apoptotic cells (ACs), is critical in preventing necrosis of dead cells and triggers anti‐inflammatory and pro‐resolving responses in phagocytes. Defects in mitochondrial fission and in electron transport chain function result in impaired efferocytosis, which promotes progression of atherosclerosis. We hypothesized that the 2‐AAA pathway relates to atherosclerosis through modulation of macrophage efferocytosis. Our objective was to investigate the effect of 2‐AAA stimulation on macrophage efferocytosis of ACs in mouse bone‐marrow derived macrophages. We found that treatment with 2‐AAA at physiologically‐relevant doses (30µM and 100µM) for times ranging from 30 minutes to 6 hours led to consistent reductions in macrophage efferocytosis (P<0.001), suggesting a pivotal role of 2‐AAA in efferocytosis. In a human sample (N=60), we measured plasma levels of 2‐AAA and lipid profiles and found a significant negative correlation between 2‐AAA and HDL cholesterol (P<0.0001), and a significant positive correlation with triglycerides (P=0.006), further highlighting the relationship between 2‐AAA and cardiovascular risk. Our data suggest that 2‐AAA is associated with macrophage efferocytosis, potentially through impairing macrophage mitochondrial function. These novel data establish a role for the 2‐AAA pathway in efferocytosis, and could provide a new target for the treatment of atherosclerosis.