Chemokines in myocardial failure – pathogenic importance and potential therapeutic targets
Chemokines are small peptides that are potent chemoattractants for different leucocyte subpopulations and also have biological effects on certain other cell types such as endothelial cells, fibroblasts and vascular smooth muscle cells [1]. The chemokine superfamily is divided into four groups (CXC, CX3C, CC and C) according to the relative positioning of the first two closely paired and highly conserved cysteines of the amino acid sequence [1]. Their actions are mediated by a family of seven-transmembrane spanning, G-protein-coupled receptors, the size of which has grown considerably in recent years and now includes 18 members [2]. A major role of chemokines is the recruitment and activation of specific subpopulations of leucocytes, playing a pivotal role in the immune response and inflammation. While chemokine-dependent functions are essential for the control of infection, wound healing and haematopoiesis, excessive chemokine activation may result in inappropriate inflammation leading to cell and tissue damage. Thus, chemokines have been suggested to play a pathogenic role in several immune-mediated and inflammatory disorders such as bronchial asthma, inflammatory bowel disease, rheumatoid arthritis, allograft rejection, encephalomyelitis and infection with human immunodeficiency virus [1,2]. Recently, chemokines have also been implicated in the pathogenesis of several cardiovascular disorders. 
 
Chemokines – established pathogenic role in atherogenesis 
The involvement of chemokines in the pathogenesis of atherosclerosis has been widely investigated and raised chemokine levels have been found both in plasma and in the atherosclerotic vessel itself. Thus, raised plasma levels of several chemokines (e.g. interleukin (IL)-8, monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-1α) have been found in patients with coronary artery disease, with the highest levels in those with acute coronary syndromes [3]. Moreover, enhanced expression of several chemokines (e.g. IL-8, MCP-1 and interferon inducible protein 10 (IP-10)), has been found in human atherosclerotic lesions, possibly mediating chemoattractant and mitogenic effects on neutrophils, T cells and smooth muscle cells [4,5]. Furthermore, macrophages with enhanced expression of chemokine receptors (e.g. CXCR2 and CCR2) have been reported in advanced murine and human atheroma [4]. Also, knock-out mice lacking these receptors or their corresponding ligands (i.e. IL-8 and MCP-1) have significantly reduced progression of atherosclerosis [6–8].