Production of Chemokines by Perivascular Adipose Tissue

Abstract

Objective-Obesity is associated with an increased risk for cardiovascular disease. Although it is known that white adipose tissue (WAT) produces numerous proinflammatory and proatherogenic cytokines and chemokines, it is unclear whether adipose-derived chemotactic signals affect the chronic inflammation in atherosclerosis. Methods and Results-Histological examination showed that perivascular WAT (pWAT) is in close proximity to vascular walls, particularly at sites that have a tendency to develop atherosclerosis. In rodents, the amount of pWAT is markedly increased by a high-fat diet. At a functional level, supernatant from subcutaneous and pWAT strongly induced the chemotaxis of peripheral blood leukocytes. The migration of granulocytes and monocytes was mostly mediated by interleukin-8 and monocyte chemoattractant protein-1, respectively, whereas both chemokines contributed to the migration of activated T cells. Moreover, pWAT produces these chemokines, as shown by immunohistochemistry and by explant culture. The accumulation of macrophages and T cells at the interface between pWAT and the adventitia of human atherosclerotic aortas may reflect this prochemotactic activity of pWAT. Conclusions-Human pWAT has chemotactic properties through the secretion of different chemokines, and we propose that pWAT might contribute to the progression of obesity-associated atherosclerosis. (Arterioscler Thromb Vasc Biol. 2005;25:2594-2599.)Key Words: chemokines Ⅲ perivascular adipose tissue Ⅲ chemotaxis Ⅲ obesity Ⅲ inflammation O besity is characterized by an excess of body fat and is associated with an increased risk for cardiovascular disease. 1 Obesity is also linked to a state of chronic inflammation 2 associated with the production of pro-and antiinflammatory cytokines secreted by white adipose tissue (WAT), such as interleukin (IL)-6, tumor necrosis factor (TNF)-␣, IL-1␤, and the IL-1 receptor antagonist. 3 WAT is also known to produce chemokines such as IL-8 (also called CXCL8) 4,5 and monocyte chemoattractant protein-1 (MCP-1, also called CCL2). 5,6 Atherosclerosis is characterized by the accumulation of macrophages and T lymphocytes in the wall of large arteries, a process in which chemokines play an important role. 7,8 Many of the chemoattractant factors involved in the development of atherosclerosis are expressed in the atherosclerotic plaque and produced by endothelial and smooth muscle cells. 8 The importance of chemokines in the development of atherosclerosis has been demonstrated in a low-density lipoprotein (LDL) receptor-deficient mouse model where the invalidation of the MCP-1 gene prevented lipid deposition and macrophage infiltration in the aortic wall. 8 Similarly, irradiated LDL receptor-deficient mice received a transplant of bone marrow cells lacking the CXCR2 (murine IL-8 homologue receptor), resulting in the reduced accumulation of monocytes/macrophages in the vascular intima. 9 Because obesity is a metabolic and chronic inflammatory condition associated with cardiovascular complications, it is tempti...

Distribution of Inflammatory Cells in Adventitia Changed with Advancing Atherosclerosis of Human Coronary Artery

“…Ramshaw and Parums followed and confirmed this in 1990 1) . In recent years, several reports have been published about adventitis accompanying atherosclerosis 15,[17][18][19][20] , but no reports have tried to elucidate the transition of the distribution of infiltrating inflammatory cells in the adventitia with advancing atherosclerosis. In the present study, T lymphocyte marker (CD45RO, CD4, CD8)-positive cells decreased in type , which might suggest that the original inflammatory response subsided in type and different or other inflammatory stimuli were induced in type .…”

“…Schwartz reported lymphocyte accumulation in the adventitia of atherosclerosis in 1962 16) . In recent years, reports have increased about adventitis accompanying atherosclerosis and it is still unclear whether B lymphocytes or T lymphocytes are dominant 1,15,[17][18][19][20] . The possibility remains of the transition of infiltrating cells as the type of atherosclerosis advances, but no reports have tried to elucidate the relationship between the stage of atherosclerosis and the distribution of inflammatory cells in adventitia in human atherosclerosis.…”

Epicardial adipose tissue: at the heart of the obesity complications

“…In addition, the mRNA levels of secretory type II phospholipase A2 (sPLA2-IIA), an enzyme promoting the generation of more atherogenic low-density lipoproteins and phospholipid products in the artery wall and their retention of in the subendothelial space, have been found increased in EAT from CAD patients [18]. In CAD conditions, as shown by proteomic and secretome analyses, EAT-derived mediators are capable of inducing cell surface expression of adhesion molecules in monocytes and endothelial cells [44], and FFAs released by EAT in the proximity of coronary arteries can modulate vascular responsiveness to vasoactive agents [45]. Contrariwise, EAT anti-inflammatory and anti-atherogenic adipokines (adiponectin and adrenomedullin) are down-regulated in chronic CAD, and increase in intracoronary adrenomedullin levels has been reported only when hemodynamic conditions improve as after coronary revascularization [25,26] (Fig.…”

Enhanced Inflammation in Epicardial Fat in Patients With Coronary Artery Disease

“…3) Recent reports showed that periadventitial fat secretes various chemokines that might contribute to the progression of obesity-associated atherosclerosis. 4) Epicardial adipose tissue (EAT) is located in close proximity to coronary arteries. EAT has been reported to be a source of inflammatory mediators.…”