Leukocyte Overexpression of Intracellular NAMPT Attenuates Atherosclerosis by Regulating PPARγ-Dependent Monocyte Differentiation and Function
Leukocyte Overexpression of Intracellular NAMPT Attenuates Atherosclerosis by Regulating PPARγ-Dependent Monocyte Differentiation and Function
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DOI：
10.1161/atvbaha.116.308187
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发表时间：
2017-06-01
影响因子：
8.7
通讯作者：
Leonardus Biessen, Erik Anna
中科院分区：
文献类型：
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作者：
Bermudez, Beatriz;Dahl, Tuva Borresdatter;Leonardus Biessen, Erik Anna
目的：细胞外烟酰胺磷酸核糖基转移酶（eNAMPT）介导炎症和潜在的促动脉粥样硬化作用，而细胞内NAMPT （iNAMPT）在烟酰胺腺嘌呤二核苷酸（NAD）（+）生成的挽救途径中的限速酶在动脉粥样硬化中的作用在很大程度上是未知的。我们研究了白细胞中iNAMPT过表达对炎症和动脉粥样硬化的影响。方法和结果-低密度脂蛋白受体缺陷小鼠造血过表达人iNAMPT(iNAMPT(hi))，在西式饮食中表现出斑块负担减轻和病变稳定的特征。这种抗动脉粥样硬化作用是通过减弱趋化因子（C-C基序）受体2依赖性单核细胞趋化性和使巨噬细胞极化向抗炎M2表型倾斜来改善巨噬细胞对凋亡的抵抗。用NAMPT抑制剂FK866治疗后，iNAMPT（hi）表型几乎完全逆转，表明iNAMPT的催化活性在动脉粥样硬化保护中起重要作用。重要的是，iNAMPT过表达不会诱导eNAMPT的增加，并且eNAMPT对趋化因子（C-C基序）受体2的表达没有影响，并促进巨噬细胞的炎症M1表型。inampt介导的效应至少部分涉及sirtuin 1依赖的NAMPT和过氧化物酶体增殖物激活受体的分子串扰。最后，iNAMPT和过氧化物酶体增殖物激活受体。在人类动脉粥样硬化中显示出很强的相关性，但在健康动脉中没有，暗示了iNAMPT/过氧化物酶体增殖物激活受体的相关性。在人类颈动脉粥样硬化中也是如此。结论：本研究强调了细胞内和细胞外NAMPT的功能二分法，并揭示了inampt -过氧化物酶体增殖物激活受体的关键作用。动脉粥样硬化轴。
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.. Finally, iNAMPT and peroxisome proliferator-activated receptor. showed a strong correlation in human atherosclerotic, but not healthy arteries, hinting to a relevance of iNAMPT/peroxisome proliferator-activated receptor. 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. axis in atherosclerosis.