MCP-1/CCL2 protects cardiac myocytes from hypoxia-induced apoptosis by a Gαi-independent pathway

Tarzami, Sima T.; Calderon, Tina M.; Deguzman, Arnel; Lopez, Lillie; Kitsis, Richard N.; Berman, Joan W.

doi:10.1016/j.bbrc.2005.07.168

Cited by 54 publications

(41 citation statements)

References 43 publications

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“…Although the importance of CCL2 as a major chemoattractant of mononuclear cells to the ischemic heart has been extensively studied, the results are often in conflict, with both administration and inhibition of CCL2 showing improvements and detrimental effects in the remodeling following MI (19,20). These discrepancies may be a result of the timing of administration or inhibition, because short-term elevations in CCL2 are protective whereas sustained elevations in CCL2 contribute to an enhanced progression toward heart failure (21)(22)(23)(24). Indeed, studies examining the involvement of CCR2 following cardiac injury have shown beneficial effects with CCR2 inhibition (25)(26)(27), wherein both global and monocyte-directed RNAi-mediated deletion of CCR2 in mice that underwent MI surgery resulted in improved left ventricular remodeling (25,26).…”

Section: Discussionmentioning

confidence: 99%

β2-Adrenergic receptor-dependent chemokine receptor 2 expression regulates leukocyte recruitment to the heart following acute injury

Grisanti

Traynham

Repas

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Following cardiac injury, early immune cell responses are essential for initiating cardiac remodeling and tissue repair. We previously demonstrated the importance of β2-adrenergic receptors (β2ARs) in the regulation of immune cell localization following acute cardiac injury, with deficient leukocyte infiltration into the damaged heart. The purpose of this study was to investigate the mechanism by which immune cell-expressed β2ARs regulate leukocyte recruitment to the heart following acute cardiac injury. Chemokine receptor 2 (CCR2) expression and responsiveness to C-C motif chemokine ligand 2 (CCL2)-mediated migration were abolished in β2AR knockout (KO) bone marrow (BM), both of which were rescued by β2AR reexpression. Chimeric mice lacking immune cell-specific CCR2 expression, as well as wild-type mice administered a CCR2 antagonist, recapitulated the loss of monocyte/macrophage and neutrophil recruitment to the heart following myocardial infarction (MI) observed in mice with immune cell-specific β2AR deletion. Converse to β2AR ablation, β2AR stimulation increased CCR2 expression and migratory responsiveness to CCL2 in BM. Mechanistically, G proteindependent β2AR signaling was dispensable for these effects, whereas β-arrestin2-biased β2AR signaling was required for the regulation of CCR2 expression. Additionally, activator protein 1 (AP-1) was shown to be essential in mediating CCR2 expression in response to β2AR stimulation in both murine BM and human monocytes. Finally, reconstitution of β2ARKO BM with rescued expression of a β-arrestin-biased β2AR in vivo restored BM CCR2 expression as well as cardiac leukocyte infiltration following MI. These results demonstrate the critical role of β-arrestin2/AP-1-dependent β2AR signaling in the regulation of CCR2 expression and recruitment of leukocytes to the heart following injury.β2-adrenergic receptor | leukocyte | C-chemokine receptor 2 | cardiac injury | β-arrestin

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Section: Discussionmentioning

confidence: 99%

β2-Adrenergic receptor-dependent chemokine receptor 2 expression regulates leukocyte recruitment to the heart following acute injury

Grisanti

Traynham

Repas

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…33,34 We found that chronic expression of MCP-1 in cardiomyocytes leads to ischemic heart disease that manifests the clinical, pathological, ultrastructural, and molecular features found in human ischemic heart disease. 18,19 How chronic inflammation and prolonged exposure of the myocardium to elevated levels of MCP-1 cause heart failure remains unclear.…”

Section: Discussionmentioning

confidence: 99%

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

Zhou

Azfer

Niu

et al. 2006

Circulation Research

235

259

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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...

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“…Conversely, CXCL8 inhibits neutrophil apoptosis (31) and induces B cell chronic lymphocytic leukemia cell accumulation (32). It has also been suggested that CCL2 might regulate pancreatic cancer progression (33), protect cardiac myocytes from hypoxia-induced apoptosis (34), and inhibit activation-induced cell death in HIV-infected individuals (35).…”

Section: Discussionmentioning

confidence: 99%

CCL2 Inhibits the Apoptosis Program Induced by Growth Factor Deprivation, Rescuing Functional T Cells

Díaz-Guerra

Vernal

Prete

et al. 2007

The Journal of Immunology

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The precise mechanisms involved in the switch between the clonal expansion and contraction phases of a CD8+ T cell response remain to be fully elucidated. One of the mechanisms implicated in the contraction phase is cytokine deprivation, which triggers apoptosis in these cells. CCR2 chemokine receptor is up-regulated following IL-2 deprivation, and its ligand CCL2 plays an essential role preventing apoptosis induced by IL-2 withdrawal not only in CTLL2 cells, but also in mouse Ag-activated primary CD8+ T cells because it rescued functional CD8+ T cells from deprivation induced apoptosis, promoting proliferation in response to subsequent addition of IL-2 or to secondary antigenic challenges. Thus, up-regulation of the CCR2 upon growth factor withdrawal together with the protective effects of CCL2, represent a double-edged survival strategy, protecting cells from apoptosis and enabling them to migrate toward sites where Ag and/or growth factors are available.

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MCP-1/CCL2 protects cardiac myocytes from hypoxia-induced apoptosis by a Gαi-independent pathway

Cited by 54 publications

References 43 publications

β2-Adrenergic receptor-dependent chemokine receptor 2 expression regulates leukocyte recruitment to the heart following acute injury

β2-Adrenergic receptor-dependent chemokine receptor 2 expression regulates leukocyte recruitment to the heart following acute injury

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

CCL2 Inhibits the Apoptosis Program Induced by Growth Factor Deprivation, Rescuing Functional T Cells

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