The anti-inflammatory vasostatin-2 attenuates atherosclerosis in ApoE-/- mice and inhibits monocyte/macrophage recruitmentFinancial support: This work was supported by the grants from Chinese Natural Science Foundation (81070178, 81370256 and 91539117), Shanghai Science and Technology Key Project (12JC1406300) and Shanghai Municipal Education CommissionGaofeng Clinical Medicine Grant (20152205).
Received:27 June 2016
Accepted after major revision:18 October 2016
13 November 2017 (online)
We showed previously that reduced level of vasostatin-2 (VS-2) correlates to the presence and severity of coronary artery disease. In this study, we aimed to figure out the role of chromogranin A (CGA) derived VS-2 in the development of atherosclerosis and monocyte/macrophage recruitment. Apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat diet exhibited attenuated lesion size by 65 % and 41 % in En face and aortic root Oil red O staining, MOMA-2 positive area by 64 %, respectively, in VS-2 treatment group compared with PBS group. Proinflammatory cytokines tumour necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) were all remarkably reduced in aortic tissues after VS-2 treatment. Mechanistically, in adhesion assay using intravital microscopy in vivo, VS-2 suppressed the number of leukocytes adhering to the wall of apoE-/- mice mesenteric arteries. In chemotactic assay, flow cytometry analysis of peritoneal lavage exudate from C57BL/6 mice showed VS-2 significantly decreased the recruiment number of inflammatory monocytes/macrophages in a thioglycollate-induced peritonitis model. Furthermore, fewer fluorescent latex beads labelled Ly-6Chi monocytes accumulated in aortic sinus lesions of apoE-/- mice after VS-2 treatment. In addition, according to the microarray of human monocyte/macrophage, we found VS-2 stimulation caused a dose-dependent decrease of Rac1 expression and inactivation of Pak1 in mice primary monocytes as well as THP-1 cells and inhibited MCP-1/CCL-5 induced transmigration in vitro. In conclusion, the Chromogranin A-derived VS-2 attenuates atherosclerosis in apoE-/- mice and, in addition to its anti-inflammatory property, also acts as an inhibitor in monocyte/macrophage recruitment.
Supplementary Material to this article is available online at www.thrombosis-online.com.
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