See article by Damås et al. [16] (pages 428–436) in this issue. Recruitment of circulating leukocytes requires a variety of soluble and cell-associated factors, which mediate their migration into injured or inflamed tissues. Chemokines (chemotactic cytokines) are low-molecular-weight (8–10 kiloDaltons) proteins characterized by their ability to induce directional migration of leukocytes, thought to play important roles in controlling inflammation and immune responses [1,2]. Chemokines mediate not only the migration but also the growth and activation of leukocytes and other cells. They are produced by a variety of cell types of hematopoietic and nonhematopoietic origin in response to antigens, polyclonal stimulants, cell irritants, and cytokines, and their biologic effects are mediated by the interaction of these soluble proteins with members of the superfamily of seven transmembrane domain G protein-coupled receptors [3]. The largest chemokine subfamilies are designated C–C and C–X–C, according to the spacing of the first two of four conserved cysteine residues [1,2]. Two other subfamilies have been identified: the C chemokines (which lack the first and third of the conserved cysteine residues) and transmembrane chemokines with an active CX3C motif on top of a mucin stalk [4,5]. Chemokines are capable of heparin binding at their C-terminal end, which enables them to bind to glycosaminoglycan and other negatively charged sugar moieties on cell surfaces and matrix glycoproteins [6]. This property may result in their adsorption onto endothelial cell lining of the blood vessels, connective tissues and cell matrices. Thus, chemokines immobilized on tissue or matrix surfaces may induce “haptotactic” migration of target cells. Recent studies have revealed that chemokines play a pivotal role in host defense and in inflammatory or immunological conditions such as ischemic reperfusion injury, adult respiratory distress syndrome, autoimmune reactions and malignant tumors [2,7]. Furthermore, there is growing evidence to suggest that chemokines play an important pathogenic role in cardiovascular diseases. The involvement of chemokines in the pathogenesis of atherosclerosis has been widely investigated, and its central role in the process has been clearly clarified. Migration of monocytes is thought to be the earliest and most significant event in the formation of atherosclerotic lesions. Monocyte recruitment to the vessel wall is mainly regulated by chemokines, particularly monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 (MCP-1). In response to several atherogenic stimulants such as oxidized low density lipoprotein (LDL), CD40 ligand, platelet-derived growth factor and interleukin-1β (IL-1β), MCP-1 is induced in endothelial cells, smooth muscle cells and monocytes and promotes the transmigration of monocytes through the endothelial barrier [8]. The main role of MCP-1 in atherogenesis is supported by the observation that additional depletion of the MCP-1 receptor C–C chemokine receptor (CCR2) markedly attenuated atherosclerotic lesions by inhibiting macrophage accumulation in apolipoprotein E (ApoE) deficient mice [9]. Furthermore, we recently reported that neutralization of MCP-1 before, and immediately after arterial injury may be effective in preventing restenosis after angioplasty [10]. Clinical studies have shown that circulating levels of C–C chemokines and C–X–C chemokines were increased in patients with acute myocardial infarction [11,12], suggesting that they are important mediators in ischemia-induced myocardial injury. In canine model, Kukielka et al. found that IL-8, a member of C–X–C chemokines, is prominently and consistently induced after myocardial ischemia/reperfusion, and that IL-8 participates in neutrophil-mediated myocardial injury [13]. Recently, we have reported that MCP-1, another member of the chemokines family, is also induced by myocardial ischemia/reperfusion, and that neutralization of MCP-1 significantly reduces infarct size at 24 h after reperfusion [14]. Thus, chemokines are considered to be important mediators in ischemic myocardial injury, and they may become a prime target in the management of ischemia-induced myocardial injury. Aukrust et al. have reported that circulating levels of C–C chemokines were increased in patients with congestive heart failure [15], and have suggested that they were involved not only in the pathogenesis of atherosclerosis and ischemia-induced myocardial injury, but also in the development of congestive heart failure. In this issue of the Journal, Damås et al. show that circulating levels of C–X–C-chemokines, IL-8, growth-regulated oncogene-α, and epithelial neutrophil activating peptide (ENA)-78, gradually increased in patients with congestive heart failure in parallel with an increase in New York Heart Association functional class [16]. The authors also report that activated platelets stimulated peripheral blood mononuclear cells in vitro, and enhanced the release of IL-8, and that neutralizing antibodies against ENA-78 inhibited this interaction. Thus, the interaction between activated platelets and monocytes may be important in heart failure, though further studies of the myocardial expression of chemokines are needed. We have recently obtained experimental results that demonstrate the role of chemokines in the initiation of congestive heart failure. In the pressure-overloaded ventricle, the myocardium initially developed adaptive hypertrophy, which, at a later stage evolved towards heart failure. To determine the involvement of proinflammatory cytokines and MCP-1 in congestive heart failure induced by mechanical overload, we measured the expression of cytokines and MCP-1 in the left ventricle of Dahl salt-sensitive rats that had developed hypertensive left ventricular hypertrophy and, subsequently, congestive heart failure [17]. The mRNA levels of MCP-1 in the left ventricle was already increased at the hypertrophic stage (before the onset of congestive heart failure) and, concordantly, the number of interstitial macrophages had increased diffusely throughout the left ventricle. MCP-1 protein was localized to the endothelial cells and interstitial macrophages. These increased macrophages were the main source of IL-1β, which was positively correlated with the left ventricular weight/body weight ratio, and which was thought to mediate the progression of heart failure. It has been suggested that mechanical overload induces the expression of chemokines, which attract and activate monocytes and macrophages, and that these recruited cells produce proinflammatory cytokines which contribute to the pathogenesis of heart failure. How does mechanical overload upregulate the expression of chemokines? When cyclic mechanical stretch was applied to the endothelial cells of human umbilical veins, cultured on flexible silicone membranes, levels of MCP-1 and IL-8 in the culture medium increased significantly [18]. Northern blot analysis showed that mRNA levels of MCP-1 and IL-8 were upregulated by cyclic stretch as a function of its intensity. Likewise, endothelial cells in the myocardium may sense mechanical overload and induce chemokine expression. A growing number of studies have indicated that chemokines are key mediators of several cardiovascular disorders. A series of antagonists have been recently produced which block the pathological effects of chemokines, and antichemokine antibody and peptide analogues which compete with native ligands for binding sites have been found effective to prevent the development of several pathological states [19,20]. Therefore, further in vivo studies of chemokine antagonists will offer new therapies for cardiovascular diseases. As more is being discovered about the pathophysiologic and pathogenetic roles of chemokines in heart failure, the design of better and more targeted pharmacological agents should become a reality.
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S Sasayama (2000) studied this question.