The role of the chemokines, MIP -2 and JE /MCP -1, in myocardial ischemia

Abstract

Chemokines are small molecular weight proteins that are important in inflammation. Originally described as chemotactic cytokines, chemokines have now been demonstrated to activate gene expression in nonhematopoetic cells and to mediate a vast array of cellular functions in addition to chemotaxis. This study was to examine the expression and role of chemokines in myocardial ischemia. It was our hypothesis that two such chemokines, MIP-2 and JE/MCP-1, serve a dual role in the ischemia/reperfusion processes of the heart: (1) to protect cardiac myocytes from the early effects of ischemia-induced apoptosis and (2) to recruit inflammatory cells into the reperfused heart, thereby contributing to the inflammation-mediated damage or protection often associated with reperfusion.;We used an ischemia without reperfusion model to investigate the role of chemokines in myocardial ischemia prior to leukocyte infiltration. Mice were subjected to coronary ligation and were sacrificed at several time points. Chemokine and chemokine receptor expression was induced as early as 1 hr post ischemia with most significant increases in JE/MCP-1 and MIP-2. Expression of their respective receptors, CCR2 and CXCR2, was also induced with ischemia. Using a tissue culture model, we demonstrated that neonatal cultured myocytes, stimulated by hypoxia express the chemokines, in particular JE/MCP-1 and MIP-2.;Intracardiac administration of either rMIP-2 or adMIP-2 upregulates JE/MCP-1 production in the heart in vivo in the absence of any ischemia. In addition, we showed that rJE/MCP-1 protects cultured myocytes from hypoxia-induced cell death. This protection was not through the activation of Gai pathway; thus, it is a pertussis toxin insensitive mechanism. This differs from JE/MCP-1 signaling that mediates monocyte chemotaxis, which is PTX sensitive.;Inhibition of the ERK1/2 signaling pathway abrogated the JE/MCP-1 protective effect. In addition, treatment of myocytes with rJE/MCP-1 during hypoxia reduced Caspase 3 activation. JE/MCP-1-treated cultured myocytes subjected to hypoxia had higher expression of Bcl-xl and Bag-1 proteins, the antiapoptotic members of the Bcl-2 family and down regulation of Bax protein, a proapoptotic member of the Bcl-2 family protein. These proteins are important in modulating mitochondria integrity and subsequent activation of down stream caspases. These findings indicate a role for MIP-2 in regulating JE/MCP-1 production in vivo and also demonstrate an important role for JE/MCP-1 in protecting myocytes from ischemic injury.;We conclude that loss of cardiac myocytes plays an important role in the pathogenesis of cardiac disease, and that loss of cardiomyocytes is, a major contributor to heart disease progression. Therefore, the role of JE/MCP-1 in inhibiting myocytes apoptosis is of major interest in order to develop novel interventional treatment strategies.