更新于：2024-11-01

NAMPT x CCR2

更新于：2024-11-01

基本信息

关联

项与 NAMPT x CCR2 相关的药物

MM015

靶点

CCR2 x NAMPT

作用机制

CCR2拮抗剂 [+1]

在研机构

The University of Manchester

原研机构

The University of Manchester

在研适应症

慢性粒单核细胞白血病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 NAMPT x CCR2 相关的临床结果

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100 项与 NAMPT x CCR2 相关的转化医学

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0 项与 NAMPT x CCR2 相关的专利（医药）

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项与 NAMPT x CCR2 相关的文献（医药）

2017-06-01·Arteriosclerosis, Thrombosis, and Vascular Biology1区 · 医学

Leukocyte Overexpression of Intracellular NAMPT Attenuates Atherosclerosis by Regulating PPARγ-Dependent Monocyte Differentiation and Function

1区 · 医学

Article

作者: Nagy, Laszlo ; Muriana, Francisco J.G. ; Rousch, Mat ; Holm, Sverre ; Abia, Rocio ; Bermudez, Beatriz ; Yndestad, Arne ; Herias, Veronica ; Aukrust, Pal ; Biessen, Erik Anna Leonardus ; Varela, Lourdes M. ; Montserrat-de la Paz, Sergio ; Otten, Jeroen ; Groeneweg, Mathijs ; Ortega-Gomez, Almudena ; Medina, Indira ; Dahl, Tuva Borresdatter ; Halvorsen, Bente ; Ranheim, Trine

Objective— Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) mediates inflammatory and potentially proatherogenic effects, whereas the role of intracellular NAMPT (iNAMPT), the rate limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide (NAD) + generation, in atherogenesis is largely unknown. Here we investigated the effects of iNAMPT overexpression in leukocytes on inflammation and atherosclerosis. Approach and Results— Low-density lipoprotein receptor–deficient mice with hematopoietic overexpression of human iNAMPT (iNAMPT hi ), on a western type diet, showed attenuated plaque burden with features of lesion stabilization. This anti-atherogenic effect was caused by improved resistance of macrophages to apoptosis by attenuated chemokine (C–C motif) receptor 2-dependent monocyte chemotaxis and by skewing macrophage polarization toward an anti-inflammatory M2 phenotype. The iNAMPT hi phenotype was almost fully reversed by treatment with the NAMPT inhibitor FK866, indicating that iNAMPT catalytic activity is instrumental in the atheroprotection. Importantly, iNAMPT overexpression did not induce any increase in eNAMPT, and eNAMPT had no effect on chemokine (C–C motif) receptor 2 expression and promoted an inflammatory M1 phenotype in macrophages. The iNAMPT-mediated effects at least partly involved sirtuin 1–dependent molecular crosstalk of NAMPT and peroxisome proliferator–activated receptor γ. Finally, iNAMPT and peroxisome proliferator–activated receptor γ showed a strong correlation in human atherosclerotic, but not healthy arteries, hinting to a relevance of iNAMPT/peroxisome proliferator–activated receptor γ pathway also in human carotid atherosclerosis. Conclusions—This study highlights the functional dichotomy of intracellular versus extracellular NAMPT, and unveils a critical role for the iNAMPT–peroxisome proliferator–activated receptor γ axis in atherosclerosis.

2009-07-01·Atherosclerosis2区 · 医学

Pre-B cell colony enhancing factor (PBEF)/visfatin induces secretion of MCP-1 in human endothelial cells: Role in visfatin-induced angiogenesis

2区 · 医学

Article

作者: Bee K. Tan ; Harpal S. Randeva ; Jing Chen ; Raghu Adya

OBJECTIVESVisfatin and Monocyte-Chemoattractant-Protein-1 (MCP-1) are elevated in cardiovascular pathologies, insulin-resistant and diabetic states. Visfatin has been reported to exhibit pro-angiogenic actions in human endothelial cells. Given MCP-1's well described pro-angiogenic properties we sought to study the potential interaction between visfatin and MCP-1 in human endothelial cells. We also explored the possible autocrine/paracrine mechanisms governing this potential interaction; specifically we looked at the effect of visfatin on MCP-1's putative receptor (CCR2 receptor) in human endothelial cells.METHODS AND RESULTSUsing in vitro angiogenic assays (capillary tube formation and migration), Western blotting and RT-PCR, we found that visfatin, dose-dependently, induced MCP-1 as well as CCR2 levels. We also studied the involvement of PI3Kinase, MAPKinase and NF-kappaB pathways in visfatin induced MCP-1/CCR2 levels by employing LY294002, U0126 and BAY11-7085, respectively. We found the increase in MCP-1 and CCR2 levels by visfatin were negated by LY294002 and BAY11-7085, but not with U0126, suggesting the crucial role of PI3Kinase and NF-kappaB pathways in visfatin induced MCP-1 and its autocrine regulation via the CCR2 receptor. Finally, we consolidate the role of MCP-1 in visfatin-induced angiogenesis by employing CCR2 antagonist (RS-102895) and MCP-1 neutralising antibody, respectively.CONCLUSIONSOur novel data reveal that MCP-1 is pivotal in modulating visfatin-induced angiogenesis via NF-kappaB and PI3Kinase pathways. Furthermore, our findings elucidate the potential influence of autocrine/paracrine mechanisms (via the CCR2 receptor) underlying visfatin's angiogenic effects through MCP-1.