Chemokines in the Pathogenesis of Vascular Disease

Abstract

Abstract-Our increasing appreciation of the importance of inflammation in vascular disease has focused attention on the molecules that direct the migration of leukocytes from the blood stream to the vessel wall. In this review, we summarize roles of the chemokines, a family of small secreted proteins that selectively recruit monocytes, neutrophils, and lymphocytes to sites of vascular injury, inflammation, and developing atherosclerosis. Chemokines induce chemotaxis through the activation of G-protein-coupled receptors, and the receptors that a given leukocyte expresses determines the chemokines to which it will respond. Monocyte chemoattractant protein 1 (MCP-1), acting through its receptor CCR2, appears to play an early and important role in the recruitment of monocytes to atherosclerotic lesions and in the formation of intimal hyperplasia after arterial injury. Acute thrombosis is an often fatal complication of atherosclerotic plaque rupture, and recent evidence suggests that MCP-1 contributes to thrombin generation and thrombus formation by generating tissue factor. Because of their critical roles in monocyte recruitment in vascular and nonvascular diseases, MCP-1 and CCR2 have become important therapeutic targets, and efforts are underway to develop potent and specific antagonists of these and related chemokines. A preponderance of evidence from clinical and experimental studies supports the notion that inflammation plays an important role in a wide range of cardiovascular diseases [1][2][3][4] and has focused attention on the signals that initiate cellular infiltration of vascular tissues. The chemokines are a family of potent chemotactic cytokines that regulate the trafficking of leukocytes and are rapidly upregulated at sites of vascular inflammation. Here, we review the role of monocyte chemoattractant protein 1 (MCP-1) and related chemokines in regulating the recruitment of monocyte/macrophages to the vessel wall and discuss how these chemokines contribute to the pathophysiology of vascular disease, with an emphasis on atherosclerosis. Chemokines and Chemokine ReceptorsChemokines (chemotactic cytokines) are small heparinbinding proteins that direct the migration of circulating leukocytes to sites of inflammation or injury. 5,6 There are Ϸ50 human chemokines, which are divided into three major families based on differences in their structure and function.The largest family is known as the CC chemokines because the first two of the four conserved cysteine residues that are characteristic of chemokines are adjacent to each other. CC chemokines tend to attract mononuclear cells and are found at sites of chronic inflammation. The most thoroughly characterized CC chemokine is MCP-1 (also known as CCL2), a potent agonist for monocytes, memory T cells, and basophils. The third family, the CX3C family, has only one known member, fractalkine (FK; or CX3CL1). FK consists of a soluble chemokine domain fused to a mucin-like stalk and a transmembrane domain. Thus, unlike other soluble chemokines, it is a type 1 tran...

Anti-Atherogenic Effects of the Combination Therapy with Olmesartan and Azelnidipine in Diabetic Apolipoprotein E-Deficient Mice

“…It is, however, conceivable that the combination therapy with OLM and AZL decreases ROS production probably through eNOS activation and inhibition of RAGE and macrophage infiltration, while reduced ROS simultaneously increase NO availability, decrease RAGE and inhibit macrophage infiltration via suppression of pro-inflammatory cytokines (Fig. 7) (Tanaka et al 2000;Charo and Taubman 2004). NO scavenges superoxide and causes up-regulation of superoxide dismutase (SOD) expression (Shimokawa 1999;Kawashima and Yokoyama 2004;Vanhoutte 2009).…”

Chemokines as risk factors for type 2 diabetes: results from the MONICA/KORA Augsburg study, 1984–2002

“…Members of this class of low molecular weight proteins play key roles in inflammatory processes by regulating migration and activation of many cell types [9]. Monocyte chemoattractant protein-1 (MCP-1), IL-8 and interferon-γ-induced protein-10 (IP-10) are expressed and secreted by adipocytes [10, 11 and unpublished results] and have also been reported to be involved in atherosclerosis and obesity in animal models as well as in cross-sectional clinical studies [12]. It has been postulated that chemokine expression might be an important step in the recruitment and activation of peripheral blood leucocytes in atherosclerotic lesions [12] and adipose tissue [13].…”

“…Monocyte chemoattractant protein-1 (MCP-1), IL-8 and interferon-γ-induced protein-10 (IP-10) are expressed and secreted by adipocytes [10, 11 and unpublished results] and have also been reported to be involved in atherosclerosis and obesity in animal models as well as in cross-sectional clinical studies [12]. It has been postulated that chemokine expression might be an important step in the recruitment and activation of peripheral blood leucocytes in atherosclerotic lesions [12] and adipose tissue [13]. In particular elevated levels of MCP-1 and IL-8 may be associated with type 2 diabetes [14][15][16][17][18][19][20].…”

Monocyte chemoattractant protein-1 has prosclerotic effects both in a mouse model of experimental diabetes and in vitro in human mesangial cells

“…Although these results cannot be directly translated into day-to-day clinical practice, they provide a convincing proof of concept of the relevance of the MCP-1/CCR2 system in the pathogenesis of glomerular damage. In the context of other actions of MCP-1 in inducing monocyte/macrophage infiltration in the kidney and a similar phenomenon in atherosclerosis [50], another major complication of diabetes, these findings make the MCP-1/CCR-2 pathway an attractive target for developing new therapies directed towards reducing the burden of diabetic complications, including nephropathy.…”