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MCP-1 causes cardiomyoblast death via autophagy resulting from ER stress caused by oxidative stress generated by inducing a novel zinc-finger protein, MCPIP. Biochem J

Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA.
Biochemical Journal (Impact Factor: 4.78). 11/2009; 426(1):43-53. DOI: 10.1042/BJ20090976
Source: PubMed

ABSTRACT MCP-1 (monocyte chemotactic protein-1) plays a critical role in the development of heart failure that is known to involve apoptosis. How MCP-1 contributes to cell death involved in the development of heart disease is not understood. In the present study we show that MCP-1 causes death in cardiac myoblasts, H9c2 cells, by inducing oxidative stress which causes ER stress leading to autophagy via a novel zinc-finger protein, MCPIP (MCP-1-induced protein). MCPIP expression caused cell death, and knockdown of MCPIP attenuated MCP-1-induced cell death. It caused induction of iNOS (inducible NO synthase), translocation of the NADPH oxidase subunit phox47 from the cytoplasm to the membrane, production of ROS (reactive oxygen species), and induction of ER (endoplasmic reticulum) stress markers HSP40 (heat-shock protein 40), PDI (protein disulfide-isomerase), GRP78 (guanine-nucleotide-releasing protein 78) and IRE1alpha (inositol-requiring enzyme 1alpha). It also caused autophagy, as indicated by beclin-1 induction, cleavage of LC3 (microtubule-associated protein 1 light chain 3) and autophagolysosome formation, and apoptosis, as indicated by caspase 3 activation and TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling) assay. Inhibitors of oxidative stress, including CeO2 nanoparticles, inhibited ROS formation, ER stress, autophagy and cell death. Specific inhibitors of ER stress inhibited autophagy and cell death as did knockdown of the ER stress signalling protein IRE1. Knockdown of beclin-1 and autophagy inhibitors prevented cell death. This cell death involved caspase 2 and caspase 12, as specific inhibitors of these caspases prevented MCPIP-induced cell death. Microarray analysis showed that MCPIP expression caused induction of a variety of genes known to be involved in cell death. MCPIP caused activation of JNK (c-Jun N-terminal kinase) and p38 and induction of p53 and PUMA (p53 up-regulated modulator of apoptosis). Taken together, these results suggest that MCPIP induces ROS/RNS (reactive nitrogen species) production that causes ER stress which leads to autophagy and apoptosis through caspase 2/12 and IRE1alpha-JNK/p38-p53-PUMA pathway. These results provide the first molecular insights into the mechanism by which elevated MCP-1 levels associated with chronic inflammation may contribute to the development of heart failure.

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    • "A novel gene with zinc finger activity MCPIP (monocyte chemoattractant protein–induced protein) was shown by microarray analysis to stimulate many genes related to cell apoptosis and death in cardiac myoblast (Younce and Kolattukudy, 2010). The same authors demonstrated cardiomyocyte cell death by hyperglycemia linked to these zinc finger proteins (Younce et al., 2010), as well as its role in adipogenesis induction (Younce et al., 2009). These data demonstrate a close relationship between Zfp and some pathologic processes leading to heart impairment. "
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    • "Final data were described as fold changes against control cells. ROS production Oxidant production in OC precursor cells was assessed by measuring the oxidation of intracellular DHR123 (Molecular Probes) as described previously (Younce et al., 2010). ROS production was expressed as folds compared with control cells expressing GFP alone. "
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    • "Moreover, signaling initiated by CCL2 binding to CCR2 trigger the induction of a novel transcription factor, a zinc finger protein that can induce cell death (Zhou et al. 2006). This factor, which has been called MCP-1 induced protein (MCPIP), causes the production of reactive oxygen and nitrogen species via de induction of NADPH oxidase and inducible NO synthase and this oxidative stress causes ER stress that leads to autophagy and cell death (Younce and Kolattukudy 2010). "
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