Monocyte Chemoattractant Protein-1 Induces a Novel Transcription Factor That Causes Cardiac Myocyte Apoptosis and Ventricular Dysfunction

Abstract

Abstract-Monocyte chemoattractant protein-1 (MCP-1; CCL2)-mediated inflammation plays a critical role in the development of ischemic heart disease (IHD). However, the gene expression changes caused by signal transduction, triggered by MCP-1 binding to its receptor CCR2, and their possible role in the development of IHD are not understood. We present evidence that MCP-1 binding to CCR2 induces a novel transcription factor (MCP-induced protein [MCPIP]) that causes cell death. Gene microarray analysis showed that when expressed in hiuman embryonic kidney 293 cells, MCPIP induced apoptotic gene families before causing cell death. Mutagenesis studies showed that the structural features required for transcription factor-like activity were also required for causing cell death. Activation of caspase-3 was detected after MCPIP transfection and Z-VAD-fmk partially inhibited cell death. Cardiomyocyte-targeted expression of MCP-1 in mice caused death by heart failure at 6 months of age. MCPIP expression increased in parallel with the development of ventricular dysfunction. In situ hybridization showed the presence of MCPIP transcripts in the cardiomyocytes and immunohistochemistry showed that MCPIP was associated with the cardiomyocyte nuclei of apoptotic cardiomyocytes. CCR2 expression in cardiomyocytes increased with the development of IHD. MCPIP production induced by MCP-1 binding to CCR2 in the cardiomyocytes is probably involved in the development of IHD in this murine model. MCPIP transcript levels were much higher in the explanted human hearts with IHD than with nonischemic heart disease. These results provide a molecular insight into how chronic inflammation and exposure to MCP-1 contributes to heart failure and suggest that MCPIP could be a potential target for therapeutic intervention. nflammation is an important component of cardiovascular pathology associated with a number of types of heart diseases. However, the mechanism by which inflammation contributes to the development of cardiac dysfunction is poorly understood. 1-4 The recruitment and activation of monocytes/macrophages through monocyte chemoattractant protein-1 (MCP-1; CCL2) are thought to be important events that contribute to the initiation and pathophysiology of cardiovascular diseases. 5-7 MCP-1 is the main chemotactic factor for the migration of monocytes/macrophages and the pathogenesis of chronic inflammation. 8,9 Eliminating MCP-1 function or blockade of MCP-1/CCR2 pathway has been shown to decrease neointimal hyperplasia after injury and atherogenesis in mice 10 -14 and attenuate postischemic myocardial remodeling and heart failure. 15 In an attempt to mimic the inflammatory component implicated in the development of cardiovascular diseases, transgenic mice that express MCP-1 specifically in the heart were generated. Cardiactargeted expression of MCP-1 results in monocyte/macrophage infiltration into the heart, and the mice experience a thrombotic occlusive arteriolar vasculopathy that results in ischemia, interstitial fibrosis, ventricular cha...

Endothelial Dysfunction in Rheumatoid Arthritis

“…12 Such a possibility is supported by previous studies showing MCPIP level upregulated by MCP-1 or IL-1β in monocytes, macrophages, HEK293 and HpeG2 cells, cardiomyocytes, and ECs. 10,[12][13][14]25 Indeed, the level of C-reactive protein was positively correlated with that of MCP-1 in patient samples involved in the current study ( Figure V in the online-only Data Supplement). Elicited by multiple proinflammatory cytokines via NF-κB, MCPIP may thus be a common inflammatory mediator leading to impaired eNOS-derived NO bioavailability.…”

“…With the structural feature of a transcription factor, 10 MCPIP may transcriptionally activate these freeradical-producing proteins. Regarding the decreased eNOS phosphorylation under elevated redox stress, the MCPIPincreased reactive oxygen species level can inhibit the PTEN-PI3K pathway, thereby attenuating Akt activity.…”

Interleukin-17 (IL-17) and IL-1 Activate Translation of Overlapping Sets of mRNAs, Including That of the Negative Regulator of Inflammation, MCPIP1

“…6A). This function may serve to prevent formation of excess MCPIP1, which has been shown to cause cell death (23), and thus to balance MCPIP1 levels during inflammatory responses. Such conditions can diminish suppression mediated by the 3Ј-UTR of MCPIP1, as shown here for stimulation with IL-1 or IL-17.…”

“…MCPIP1, also named ZC3H12A or regnase-1, was identified as a protein induced by the chemokine MCP-1 (23). It can induce cell death and contributes to the pathophysiological role of MCP-1 in the development of ischemic heart disease (24).…”

Identification of a Novel Tumor Suppressor Gene p34 on Human Chromosome 6q25.1

“…Interestingly, the lysine corresponding to Lys 106 in human is conserved in all these organisms, but Drosophila . Recently published data suggest that a highly homologous human gene, ZC3H12A (59% identity), is induced by monocyte chemoattractant-1, and expression of ZC3H12A could lead to cell death (18).…”