TY - JOUR
T1 - Chemokine expression in myocardial ischemia
T2 - MIP-2 dependent MCP-1 expression protects cardiomyocytes from cell death
AU - Tarzami, Sima T.
AU - Cheng, Rendi
AU - Miao, Wenfeng
AU - Kitsis, Richard N.
AU - Berman, Joan W.
N1 - Funding Information:
This study was supported by an American Heart Association Grant-in-Aid (J.W.B. and S.T.T.) and by NIH RO1-HL60665 and RO1-HL61550 (R.N.K.). R.N.K. is the Charles and Tamara Krasne Faculty scholar in cardiovascular research at AECOM, and the recipient of the Monique Weill-Caulier Career Scientist Award. Thanks to all the members of the Berman Lab, past and present, in particular Dr Tina Calderon for her critical reading of the manuscript and for her advice on appropriate statistical approaches for our data. We appreciate the helpful suggestions of Drs Neelufar Mozaffarian and Carrie McManus in our initial studies.
PY - 2002/2/1
Y1 - 2002/2/1
N2 - Chemokines are small molecular weight proteins that play important roles in inflammation. Originally described as chemotactic cytokines, chemokines stimulate the influx of leukocytes into specific tissue compartments. These molecules also modulate gene expression in both infiltrating and resident ceils to mediate a vast array of cellular functions, and their importance in disease processes has been well documented. This study examined the expression of chemokines during myocardial ischemia and established a pathway by which two, MIP-2 and JE/MCP-1, modulate cardiac myocyte viability during this process. To focus on the direct effects of chemokines on these cells, a mouse model of ischemia without reperfusion was used. The expression of chemokines and chemokine receptors was induced in the left ventricular free wall as early as 1 h post-ischemia, with the most significant increases in MIP-2 (CXCL2) and JE/MCP-1 (CCL2). Expression of their respective receptors, CXCR2 and CCR2, was also induced. Similar changes in gene expression occurred at the mRNA and protein levels in isolated neonatal mouse cardiac myocytes stimulated by hypoxia. Antibody to MIP-2 inhibited hypoxia-induced JE/MCP-1 expression, demonstrating that MIP-2 is critical for this event. Moreover, in vivo intramyocardial injection of either an adenovirus expressing MIP-2 or the recombinant protein itself was sufficient to upregulate JE/MCP-1 production even in the absence of ischemia. Thus, MIP-2 regulates JE/MCP-1 expression both in cell culture and in vivo. Furthermore, JE/MCP-1 markedly decreased hypoxia-induced cell death in cultured cardiac myocytes. Thus, JE/MCP-1 appears to mediate an unanticipated survival pathway in target cardiac myocytes themselves. These findings indicate an important role for MIP-2 and JE/MCP-1 in regulating the response of cardiac myocytes to myocardial ischemia.
AB - Chemokines are small molecular weight proteins that play important roles in inflammation. Originally described as chemotactic cytokines, chemokines stimulate the influx of leukocytes into specific tissue compartments. These molecules also modulate gene expression in both infiltrating and resident ceils to mediate a vast array of cellular functions, and their importance in disease processes has been well documented. This study examined the expression of chemokines during myocardial ischemia and established a pathway by which two, MIP-2 and JE/MCP-1, modulate cardiac myocyte viability during this process. To focus on the direct effects of chemokines on these cells, a mouse model of ischemia without reperfusion was used. The expression of chemokines and chemokine receptors was induced in the left ventricular free wall as early as 1 h post-ischemia, with the most significant increases in MIP-2 (CXCL2) and JE/MCP-1 (CCL2). Expression of their respective receptors, CXCR2 and CCR2, was also induced. Similar changes in gene expression occurred at the mRNA and protein levels in isolated neonatal mouse cardiac myocytes stimulated by hypoxia. Antibody to MIP-2 inhibited hypoxia-induced JE/MCP-1 expression, demonstrating that MIP-2 is critical for this event. Moreover, in vivo intramyocardial injection of either an adenovirus expressing MIP-2 or the recombinant protein itself was sufficient to upregulate JE/MCP-1 production even in the absence of ischemia. Thus, MIP-2 regulates JE/MCP-1 expression both in cell culture and in vivo. Furthermore, JE/MCP-1 markedly decreased hypoxia-induced cell death in cultured cardiac myocytes. Thus, JE/MCP-1 appears to mediate an unanticipated survival pathway in target cardiac myocytes themselves. These findings indicate an important role for MIP-2 and JE/MCP-1 in regulating the response of cardiac myocytes to myocardial ischemia.
KW - Chemokines
KW - Hypoxia
KW - Myocardial ischemia
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U2 - 10.1006/jmcc.2001.1503
DO - 10.1006/jmcc.2001.1503
M3 - Article
C2 - 11851360
AN - SCOPUS:0036487316
SN - 0022-2828
VL - 34
SP - 209
EP - 221
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 2
ER -