Yin and yang of MCP-1.

Monocyte chemoattractant protein-1 (MCP-1, also known as CCL2) is a chemokine of the C-C type which recruits circulating monocytes to sites of inflammation. Over the past several years, MCP-1 has become established as a major factor in the development of atherosclerosis through its promotion of monocyte/macrophage accumulation in atherosclerotic plaques, leading in turn to chronic inflammation, smooth muscle cell proliferation, and plaque instability.1 Although not present in normal blood vessels, MCP-1 protein and mRNA are strongly expressed in areas of atherosclerosis.2,3 Knock out of the MCP-1 gene or the receptor for MCP-1, C-C chemokine receptor (CCR)-2, are associated with a decrease in the extent of atherosclerosis in murine models.4,5 MCP-1 is produced by endothelial cells, vascular smooth muscle cells, and macrophages in atherosclerotic plaques. Oxidized LDL in the arterial wall may upregulate the MCP-1 gene in vascular cells and stimulate the local adhesion of monocytes to endothelial cells.6 LDL-C has been shown to upregulate CCR-2 expression on monocytes, and monocyte CCR2 expression is dramatically increased in hypercholesterolemic patients compared with normal controls.7 There has been increasing interest in the role of MCP-1 in other inflammatory conditions, including post-ischemic inflammation. A study published in this issue of Circulation Research by Dewald et al demonstrates that MCP-1 plays an important role in the healing of necrotic areas of myocardium following coronary artery occlusion and reperfusion.8 Mice with disruption of the MCP-1 gene exhibited striking delays in the recruitment of macrophages into the healing infarct and in the replacement of injured myocytes by granulation tissue without any effect on neutrophil mobilization. MCP-1 null mice had decreased and delayed infiltration of macrophages, decreased expression of important cytokines, such as TNF , IL-1 , TGF , and IL-10, decreased macrophage differentiation, and diminished myofibroblast acculmulation (without a change in angiogenesis) within the healing infarct. These observations would suggest a beneficial role for MCP-1 in promoting infarct healing. The persistence of “mummified” myocytes and delay in formation of granulation tissue in MCP-1 null mice is reminiscent of the observations made 3 decades ago following the administration of high dose steroids in acute myocardial infarction. Patients treated with steroids had an increased incidence of myocardial rupture, leading to the abandoning of this potential therapy.9 Paradoxically, however, the study by Dewald et al found that MCP-1 null mice had less post-infarct left ventricular remodeling (less left ventricular dilatation and less impairment of left ventricular function) without a change in the size of the infarct, suggesting that MCP-1 somehow causes ventricular remodeling at the same time that it promotes infarct healing. This observation is unlikely to be a random error, since other approaches to inhibiting MCP-1, including over-expression of an N-terminal deletion mutant of the MCP-1 gene,10 or genetic deletion of the MCP-1 receptor CCR-2,11 have also resulted in less post-infarct left ventricular remodeling. The biological pathways responsible for post-infarct ventricular remodeling are complex and not fully understood. Remodeling occurs more than several weeks following an acute myocardial infarction, and is dependent in large part on the size of the infarcted region. The larger the infarct, the more likely the infarct region is to thin and become aneurysmal over time, and the noninfarcted region to stretch (related to myocyte elongation and myofiber rearrangement or “slippage”), and become hypertrophied and fibrotic. Clinically, these processes result in ventricular dilatation, reduced ventricular function, and often, chronic heart failure. Early reperfusion to salvage injured but viable myocytes and reduce the size of the infarcted region is an accepted approach for preventing post-infarct ventricular remodeling. The use of angiotensin converting enzyme inhibitors to reduce LV wall stress (although other effects of these inhibitors may also be important, such as their antiinflammatory effects) is also standard anti-remodeling therapy. Studies in animal models utilizing granulocyte colonystimulating factor (G-CSF) have suggested that ongoing apoptosis within the infarct and peri-infarct regions may contribute to ventricular remodeling, presumably by increasing the size of the infarcted region. G-CSF has been shown to limit remodeling by inducing anti-apoptotic proteins through activation of the Jak/Stat pathway.12 Probably equally important, G-CSF also appears to limit ventricular remodeling by promoting the expression of collagen in the infarcted area, perhaps through the upregulation of the “fibrotic cytokine” transforming growth factor(TGF).13 Rats with myocardial infarction treated with G-CSF had higher expression of TGFmRNA in the infarcted area at 3 days post-infarct, along with earlier peaking and higher levels of procollagen type I and III mRNA, and more prominent collagen accumulation in the infarcted area at 7 days. Presumably, enhanced expression of collagen in the infarcted segment makes the The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine Correspondence to Lewis C. Becker, MD Halsted 500, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287 Phone: 410-955-5997. Fax: 410-955-0852. E-mail [email protected] (Circ Res. 2005;96:812-814.) © 2005 American Heart Association, Inc.