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: 4.4). 11/2009; 426(1):43-53. DOI: 10.1042/BJ20090976
Source: PubMed


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.

16 Reads
  • Source
    • "Based on previous studies the role of autophagy in cell protection or cell damage is contradictory, and it is equally elusive whether autophagy is induced by ER stress (Ullman et al. 2008; Oh & Lim, 2009; Younce & Kolattukudy, 2010; Lee et al. 2012). To date, the effects of autophagy on LPS-induced cardiomyocyte apoptosis are still not clear, nor are the links between ER stress and autophagy. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Apoptosis of cardiomyocytes limits contractile efficiency of heart during sepsis. Pro-survival autophagy has been proposed as a novel mechanism to maintain normal heart function. Here, we demonstrated that autophagy was activated in the LPS (lipopolysaccharide)-treated HL-1 cells, and it counteracted LPS-induced apoptosis. We further investigated the mechanism by which LPS triggered autophagy in HL-1 cells. We discovered that Endoplasmic Reticulum (ER) stress played an important role in LPS-triggered autophagy. The ER activated a survival pathway through ER-localized transmembrane protein PERK, which was essential for LPS-induced autophagy. LPS increased expressions of GRP78, phosphorylated-PERK and phosphorylated-eIF2α. Similar results were observed after administration of tunicamycin (TM), a well known ER stressor. Most importantly, we found that 4-PBA, an inhibitor of ER stress, suppressed LPS-activated autophagy in the presence of LPS in HL-1 cells. The same results were observed after siRNA-mediated silencing of PERK protein. We also noticed that LPS-induced apoptosis appeared early at 4 h. Our findings revealed that PERK, one arm of ER stress, facilitated survival of LPS-induced HL-1 cells by promoting autophagy, and could serve as a potential therapeutic strategy to alleviate septic myocardial dysfunction. This article is protected by copyright. All rights reserved.
    Experimental physiology 06/2014; 99(10). DOI:10.1113/expphysiol.2014.079012 · 2.67 Impact Factor
    • "Indeed, it has been observed that melatonin could modulate autophagy, a highly conserved survival process in which eukaryotic cells self-digest cytosolic components to degrade long-lived proteins and organelles in response to starvation and other stresses [138]. Recent studies have shown that autophagy was involved in adipose tissue development [139], and that inhibition of autophagy by specific inhibitors decreased adipogenesis [140]. In a similar way, treatment of adipocytes with melatonin suppressed PPARgamma which is involved in the early stages of adipocyte differenciation [141]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Obesity is associated with an oxidative stress status, defined as an excessive production of reactive oxygen species (ROS) compared to the level of antioxidants acting in the natural defence systems. Several sources of ROS can be identified in obesity (e.g., mitochondrial respiratory chain, or NADPH oxidase) and could contribute to the pathogenesis of obesity. Indeed, these conditions favour the development of insulin resistance and metabolic syndrome through deregulation of adipokines and pro-inflammatory cytokines, so that it could be of interest to associate antioxidant therapeutic strategies with strategies of weight loss. Among antioxidants, melatonin holds a special place, on the one hand for its antioxidant and anti-inflammatory properties, and on the other hand for its role as a metabolic regulator. As melatonin modulates several processes involved in obesity and its related metabolic alterations, it could have a therapeutic interest in the treatment of obesity.
    Endocrine Metabolic & Immune Disorders - Drug Targets(Formerly Current Drug Targets - Immune Endocrine & Metabolic Disorders) 06/2014; 14(3). DOI:10.2174/1871530314666140604151452
  • Source
    • "Given a mediator role of ROS in the induction of autophagy, the overproduced ROS could activate autophagy to serve as a predominantly prosurvival mechanism in a setting of oxidative stress; however, the autophagy machinery might also be self-destructive when it is induced insufficiently thereby exaggerating oxidative stress. Indeed, ROS-mediated autophagy has been shown to lead to either survival or death in cardiac cells depending on stimuli and cell types [33–35]. Thus it is likely that ROS may induce either sufficient or insufficient activation of myocardial autophagy thereby protecting against or leading to, respectively, cardiac dysfunction. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The anticancer therapy of doxorubicin (Dox) has been limited by its acute and chronic cardiotoxicity. In addition to a causative role of oxidative stress, autophagy appears to play an important role in the regulation of Dox-induced cardiotoxicity. However, the underlying mechanisms remain unclear. Accordingly, we explored a role of nuclear factor erythroid-2 related factor 2 (Nrf2) in Dox-induced cardiomyopathy with a focus on myocardial oxidative stress and autophagic activity. In wild type (WT) mice, a single intraperitoneal injection of 25 mg/kg Dox rapidly induced cardiomyocyte necrosis and cardiac dysfunction, which were associated with oxidative stress, impaired autophagy, and accumulated polyubiquitinated protein aggregates. However, these Dox-induced adverse effects were exaggerated in Nrf2 knockout (Nrf2(-/-)) mice. In cultured cardiomyocytes, overexpression of Nrf2 increased the steady levels of LC3-II, ameliorated Dox-induced impairment of autophagic flux and accumulation of ubiquitinated protein aggregates, and suppressed Dox-induced cytotoxicity, whereas knockdown of Nrf2 exerted opposite effects. Moreover, the exaggerated adverse effects in Dox-intoxicated Nrf2 depleted cardiomyocytes were dramatically attenuated by forced activation of autophagy via overexpression of autophagy related gene 5 (Atg5). Thus, these results suggest that Nrf2 is likely an endogenous suppressor of Dox-induced cardiotoxicity by controlling both oxidative stress and autophagy in the heart.
    Oxidative medicine and cellular longevity 05/2014; 2014:748524. DOI:10.1155/2014/748524 · 3.36 Impact Factor
Show more

Similar Publications


16 Reads
Available from