The anti-inflammatory vasostatin-2 attenuates atherosclerosis in ApoE-/-mice and inhibits monocyte/macrophage recruitment.
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-6Chimonocytes 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.
Weixin
W
Xiong
Xiaoqun
X
Wang
Daopeng
D
Dai
Bao
B
Zhang
Lin Lu, Department of Cardiology, Ruijin Hospital, Jiao Tong University School of Medicine, Shanghai 200025, P. R. China, Tel.: +86 21 64370045, Fax: +86 21 64457177, E-mail: rjlulin1965@163.com.
Lin
L
Lu
Rong Tao, Department of Cardiology, Ruijin Hospital, Jiao Tong University School of Medicine, Shanghai 200025, P. R. China, Tel.: +86 21 64370045, Fax: +86 21 64457177, E-mail: rongtao@hotmail.com.
Rong
R
Tao
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002448:Cell Adhesion / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D053379:Chromogranin A / Q000494:pharmacology*; D018920:Coculture Techniques; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D000074085:Mice, Knockout, ApoE; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D058226:Plaque, Atherosclerotic; D015398:Signal Transduction / Q000187:drug effects; D000074084:THP-1 Cells; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020298:U937 Cells; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D000893:Anti-Inflammatory Agents; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D053379:Chromogranin A; D009479:Neuropeptides; D010446:Peptide Fragments; C484602:Rac1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C102106:vasostatin II; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein
Atherosclerosis; chemotaxis; inflammation; monocytes; vasostatin-2