MCP-1 causes cardiomyoblast death via autophagy resulting from ER stress caused by oxidative stress generated by inducing a novel zinc-finger protein, MCPIP.
MCP-1 causes cardiomyoblast death via autophagy resulting from ER stress caused by oxidative stress generated by inducing a novel zinc-finger protein, MCPIP.
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MCP-1 通过诱导新型锌指蛋白 MCPIP 产生的氧化应激引起内质网应激而导致心肌细胞死亡。
DOI：
10.1042/bj20090976
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Kolattukudy,PappachanE
中科院分区：
文献类型：
--
作者：
Younce,CraigW;Kolattukudy,PappachanE
MCP-1（单核细胞趋化蛋白-1）在心力衰竭的发展中起着关键作用，已知心力衰竭涉及细胞凋亡。MCP-1如何促进参与心脏病发展的细胞死亡尚不清楚。在本研究中，我们发现MCP-1通过诱导氧化应激，导致ER应激，通过一种新的锌指蛋白MCPIP（MCP-1诱导蛋白）导致自噬，从而导致心脏成肌细胞H9 c2细胞死亡。MCPIP的表达导致细胞死亡，MCPIP的敲低减弱了MCP-1诱导的细胞死亡。它引起诱导型一氧化氮合酶（iNOS）的诱导，NADPH氧化酶亚基phox 47从细胞质易位到细胞膜，产生活性氧（ROS），并诱导内质网应激标志物HSP 40（热休克蛋白40），PDI（蛋白质二硫化物异构酶），GRP 78（鸟嘌呤核苷酸释放蛋白78）和IRE 1 α（肌醇需要酶1α）。它还引起自噬，如beclin-1诱导、LC 3（微管相关蛋白1轻链3）裂解和自噬溶酶体形成所示，以及凋亡，如胱天蛋白酶3激活和TUNEL（末端脱氧核苷酸转移酶介导的dUTP缺口末端标记）测定所示。氧化应激抑制剂，包括CeO 2纳米颗粒，抑制ROS形成，ER应激，自噬和细胞死亡。ER应激的特异性抑制剂抑制自噬和细胞死亡，如ER应激信号蛋白IRE 1的敲低。beclin-1和自噬抑制剂的敲低阻止了细胞死亡。这种细胞死亡涉及半胱天冬酶2和半胱天冬酶12，因为这些半胱天冬酶的特异性抑制剂阻止了MCPIP诱导的细胞死亡。微阵列分析表明，MCPIP表达诱导了多种已知参与细胞死亡的基因。MCPIP引起JNK（c-Jun N-末端激酶）和p38的活化以及p53和p53上调的凋亡调节剂（p53 upregulated modulator of apoptosis）的诱导。综上所述，这些结果表明，MCPIP诱导ROS/RNS（活性氮物质）产生，引起ER应激，其通过caspase 2/12和IRE 1 α-JNK/p38-p53-JNK A途径导致自噬和凋亡。这些结果提供了对与慢性炎症相关的MCP-1水平升高可能导致心力衰竭发展的机制的第一个分子见解。
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-1induced 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 IRE1α (inositol-requiring enzyme 1α). 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 CeO2nanoparticles, 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 IRE1α–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.