Abstract
Depression is an independent risk factor for cardiovascular disease (CVD). We have previously shown that repeated social defeat (RSD) exaggerates atherosclerosis development by enhancing neutrophil extracellular trap (NET) formation. In this study, we investigated the impact of RSD on arterial thrombosis. Eight-week-old male wild-type mice (C57BL/6J) were exposed to RSD by housing with larger CD-1 mice in a shared home cage. They were subjected to vigorous physical contact daily for 10 consecutive days. After confirming depression-like behaviors, mice underwent FeCl3-induced carotid arterial injury and were analyzed after 3 h. Although the volume of thrombi was comparable between the two groups, fibrin(ogen)-positive areas were significantly increased in defeated mice, in which Ly-6G-positive cells were appreciably co-localized with Cit-H3-positive staining. Treatment with DNase I completely diminished exaggerated fibrin-rich clot formation in defeated mice. Flow cytometric analysis showed that neutrophil CD11b expression before FeCl3 application was significantly higher in defeated mice than in control mice. In vitro NET formation induced by activated platelets was significantly augmented in defeated mice, which was substantially inhibited by anti-CD11b antibody treatment. Our findings demonstrate that RSD enhances fibrin-rich clot formation after arterial injury by enhancing NET formation, suggesting that NET can be a new therapeutic target in depression-related CVD.
Highlights
Our findings suggest that neutrophil extracellular trap (NET) formation plays a crucial role in the development of atherosclerosis and in the onset of acute coronary syndrome (ACS) in patients with depression
These findings suggested that NET formation substantially contributed to fibrinrich clot formation in defeated mice, independent of increased neutrophil accumulation
Figure S5), we examined in vitro NET formation using mature Bone marrow (BM) neutrophilsmature of defeated neutrophils of defeated and control mice and thrombin-induced activated platelets from
Summary
Depression is a leading cause of disability worldwide and a major contributor to the global burden of disease [1]. Meta-analyses have shown that depression is associated with a high risk of coronary heart disease and increased mortality after myocardial infarction [2,3,4,5]. Integration of various factors is associated with atherosclerotic cardiovascular disease (CVD). The precise mechanisms of depression-related CVD development are unclear [6,7]. Previous studies have reported that socially defeated mice exhibit increased peripheral inflammatory monocytes and granulocytes [8,9]. The neutrophil–lymphocyte ratio was positively associated with the severity of depression [10]
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