EMAP-II downregulation contributes to the beneficial effects of rapamycin after vascular injury

Nührenberg, Thomas; Langwieser, Nicolas; Schwarz, Johannes; Hou, Yonghao; Frank, Pamela; Sorge, Falko; Matschurat, Susanne; Seidl, Stefan; Kastrati, Adnan; Schömig, Albert; Clauss, Matthias; Zohlnhöfer, Dietlind

doi:10.1093/cvr/cvm076

Cited by 14 publications

(14 citation statements)

References 32 publications

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“…36 Recently, a role of mTORC1 in inflammatory reactions and in the recruitment of HPCs to the site of vascular injury has widened the impact of mTORC1 activation in vascular remodeling and healing. 20 Taken together, the present study demonstrates a fundamental role of the Th1 immune response in repair and regeneration of vascular tissue after vessel injury yielding the CXCR3-dependent activation of mTORC1 as the interface between Th1 immune response and proliferative processes in vascular disease. These data may provide a rationale for the development of novel therapeutic strategies aiming at the inhibition of the CXCR3 axis.…”

Section: Cxcr3-dependent Activation Of Mtorc1 Is a Key Event In Ros Gsupporting

confidence: 61%

Novel Role of the CXC Chemokine Receptor 3 in Inflammatory Response to Arterial Injury

Schwarz

Langwieser

Bek

et al. 2009

Circulation Research

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Abstract-Atherosclerosis, restenosis, and posttransplant graft atherosclerosis are characterized by endothelial damage, infiltration of inflammatory cells, and proliferation of smooth muscle cells. The CXCR3-activating chemokines interferon-␥ inducible protein 10 (IP10) and MIG (monokine induced by interferon-␥) have been implicated in vascular repair and remodeling. The underlying molecular mechanisms, however, remain elusive. Here, we show that wire-mediated arterial injury induced local and systemic expression of IP10 and MIG, resulting in enhanced recruitment of CXCR3 ϩ leukocytes and hematopoietic progenitor cells. This was accompanied by profound activation of mammalian target of rapamycin complex (mTORC)1, increased reactive oxygen species production, apoptosis, and intimal hyperplasia. Genetic and pharmacological inactivation of CXCR3 signaling not only suppressed recruitment of inflammatory cells but also abolished mTORC1 activation, reduced reactive oxygen species generation, and blocked apoptosis of vascular cells, resulting in significant reduction of intimal hyperplasia in vivo. In vitro, stimulation of T cells with IP10 directly activated mTORC1 and induced generation of reactive oxygen species and apoptosis in an mTORC1-dependent manner. These results strongly indicate that CXCR3-dependent activation of mTORC1 directly links stimulation of the Th1 immune system with the proliferative response of intimal cells in vascular remodeling. T he impact of inflammation in atherosclerosis, the most important cause of morbidity in the Western world, has been well known for a long time. 1 Injury of the endothelium by proatherogenic factors such as free radicals, hypertension, and diabetes mellitus or by mechanical stress during percutaneous coronary intervention induces an early inflammatory reaction, resulting in infiltration of T cells and monocytes into the injured vessel. [1][2][3] This defined recruitment of inflammatory cells is essential for development of atherosclerosis and vascular remodeling in response to arterial injury. 4 Infiltration of inflammatory cells is accurately regulated by various members of the CC as well as CXC family of chemokines and their corresponding receptors. 4 The essential role of chemokines for vascular remodeling is highlighted by recent animal data suggesting that blocking chemokine/chemokine receptor interactions interferes with vascular remodeling. 5 Among other chemokine receptors, activation of the CXC chemokine receptor (CXCR)3 by interferon (IFN)-␥ inducible protein 10 (IP10) and MIG (monokine induced by IFN-␥) is critically involved in the recruitment of CXCR3-positive T helper type 1 lymphocytes (Th1 cells) in atheromas. 6 Likewise, blockade or depletion of CXCR3 severely attenuates recruitment of Th1 cells to the sites of inflammation and significantly reduces early steps of atherogenesis. 7-9 However, to date, the role of CXCR3 activation in the vascular response to arterial injury has not been investigated.The molecular mechanisms linking the Th1 immune sy...

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Section: Cxcr3-dependent Activation Of Mtorc1 Is a Key Event In Ros Gsupporting

confidence: 61%

Novel Role of the CXC Chemokine Receptor 3 in Inflammatory Response to Arterial Injury

Schwarz

Langwieser

Bek

et al. 2009

Circulation Research

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“…A significant increase over time in whole lung but a decreasing trend in tracheal aspirates suggested that EMAP II expression is localized and compartmentalized in response to hyperoxia. EMAP II has been shown to augment inflammatory cell counts (34). We proposed that the localization of EMAP II would be distributed in cells near the tracheal aspirate collection site and thus, histological analysis by co-staining .…”

Section: Emap II Levels In Lung Disease Of Prematuritymentioning

confidence: 99%

Endothelial Monocyte-Activating Polypeptide II Mediates Macrophage Migration in the Development of Hyperoxia-Induced Lung Disease of Prematurity

Lee

Lal

Persad

et al. 2016

Am J Respir Cell Mol Biol

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Myeloid cells are key factors in the progression of bronchopulmonary dysplasia (BPD) pathogenesis. Endothelial monocyte-activating polypeptide II (EMAP II) mediates myeloid cell trafficking. The origin and physiological mechanism by which EMAP II affects pathogenesis in BPD is unknown. The objective was to determine the functional consequences of elevated EMAP II levels in the pathogenesis of murine BPD and to investigate EMAP II neutralization as a therapeutic strategy. Three neonatal mouse models were used: (1) BPD (hyperoxia), (2) EMAP II delivery, and (3) BPD with neutralizing EMAP II antibody treatments. Chemokinic function of EMAP II and its neutralization were assessed by migration in vitro and in vivo. We determined the location of EMAP II by immunohistochemistry, pulmonary proinflammatory and chemotactic gene expression by quantitative polymerase chain reaction and immunoblotting, lung outcome by pulmonary function testing and histological analysis, and right ventricular hypertrophy by Fulton's Index. In BPD, EMAP II initially is a bronchial clubcell-specific protein-derived factor that later is expressed in galectin-3 1 macrophages as BPD progresses. Continuous elevated expression corroborates with baboon and human BPD. Prolonged elevation of EMAP II levels recruits galectin-3 1 macrophages, which is followed by an inflammatory state that resembles a severe BPD phenotype characterized by decreased pulmonary compliance, arrested alveolar development, and signs of pulmonary hypertension. In vivo pharmacological EMAP II inhibition suppressed proinflammatory genes Tnfa, Il6, and Il1b and chemotactic genes Ccl2 and Ccl9 and reversed the severe BPD phenotype. EMAP II is sufficient to induce macrophage recruitment, worsens BPD progression, and represents a targetable mechanism of BPD development.

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“…In the vasculature, EMAP II is increased after percutaneous coronary intervention (PCI), and EMAP II enhances the recruitment of inflammatory cells (44). Treatment with rapamycin prevents neointima formation and the increase in EMAP II expression post-PCI (27). EMAP II also inhibits angiogenesis, which can be beneficial in tumors but can be deleterious when manifest as inhibition of endothelial cell proliferation.…”

Section: Emap IImentioning

confidence: 99%

Impact of aging vs. estrogen loss on cardiac gene expression: estrogen replacement and inflammation

Pechenino

Lin

Mbai

et al. 2011

Physiological Genomics

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EMAP-II downregulation contributes to the beneficial effects of rapamycin after vascular injury

Abstract: These data suggest important yet unrecognized roles of EMAP-II and adventitial inflammation in neointima formation: Through inhibition of EMAP-II, rapamycin reduces the recruitment of inflammatory cells to the adventitia and supports an early and bland healing.

Cited by 14 publications

References 32 publications

Novel Role of the CXC Chemokine Receptor 3 in Inflammatory Response to Arterial Injury

Novel Role of the CXC Chemokine Receptor 3 in Inflammatory Response to Arterial Injury

Endothelial Monocyte-Activating Polypeptide II Mediates Macrophage Migration in the Development of Hyperoxia-Induced Lung Disease of Prematurity

Impact of aging vs. estrogen loss on cardiac gene expression: estrogen replacement and inflammation

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