Chemokine expression in myocardial ischemia: MIP-2 dependent MCP-1 expression protects cardiomyocytes from cell death

Sima T. Tarzami, Rendi Cheng, Wenfeng Miao, Richard N. Kitsis, Joan W. Berman

Research output: Contribution to journalArticle

73 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)209-221
Number of pages13
JournalJournal of Molecular and Cellular Cardiology
Volume34
Issue number2
DOIs
StatePublished - Feb 1 2002

Keywords

  • Chemokines
  • Hypoxia
  • Myocardial ischemia

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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