Induction of neutrophil gelatinase-associated lipocalin in vascular injury via activation of nuclear factor-κB
Induction of neutrophil gelatinase-associated lipocalin in vascular injury via activation of nuclear factor-κB
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DOI：
10.2353/ajpath.2006.050706
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发表时间：
2006-12-01
影响因子：
6
通讯作者：
Yan, Zhong-qun
中科院分区：
文献类型：
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作者：
Bu, De-xiu;Hemdahl, Anne-Louise;Yan, Zhong-qun
中性粒细胞明胶酶相关脂质运载蛋白（NGAL）最近已成为细胞内稳态的一种重要调节因子。血浆NGAL水平升高（可能是由于血液白细胞的活化）与动脉粥样硬化相关。然而，对于血管中NGAL表达的诱导却知之甚少。利用大鼠颈动脉损伤模型，我们发现血管成形术后内膜中NGAL被高度诱导，但腺病毒介导的核因子κB激酶β抑制因子的显性负性突变体（dnIKKβ）的表达可使其减弱。在白细胞介素 - 1β刺激下，大鼠和人血管平滑肌细胞（SMCs）中NGAL mRNA和蛋白质的表达也以核因子κB依赖的方式上调。大鼠SMC产生的NGAL在胞质中以单体和同聚体形式存在，分泌后存在于含有基质金属蛋白酶 - 9（MMP - 9）的复合物中。与NGAL水平一致，MMP - 9的蛋白水解活性在受损血管的内膜以及活化的内膜SMC的培养上清液中显著升高，但在转导了dnIKKβ的血管中降低。本研究揭示了一种先前未被认识的对血管成形术损伤的血管反应，其特征是血管平滑肌细胞中NGAL以核因子κB依赖的方式表达。此外，SMC产生的NGAL与MMP - 9相互作用，这可能是NGAL在血管修复过程中调节MMP - 9蛋白水解活性的一种机制。
Neutrophil gelatinase-associated lipocalin (NGAL) has recently emerged as an important modulator of cell homeostasis. Elevated plasma NGAL levels, possibly because of activation of blood leukocytes, are associated with atherosclerosis. However, little is known about induction of NGAL expression in blood vessels. Using a rat carotid artery injury model, we found that NGAL was highly induced in the intima after angioplasty but was attenuated by adenovirus-mediated expression of a dominant-negative mutant of inhibitor of nuclear factor (NF)-kappa B kinase beta P (dniKK beta). Expression of NGAL mRNA and protein was also up-regulated in an NF-kappa B-dependent manner in rat and human vascular smooth muscle cells (SMCs) in response to interieukin-1 beta stimulation. Rat SMC-produced NGAL was present as mono- and homomeric forms in the cytosol and in a complex containing matrix metalloproteinase-9 (MMP-9) after secretion. in agreement with levels of NGAL, proteolytic activity of MMP-9 was markedly high in the intima of injured vessels and in the culture supernatant of activated intimal SMCs but was reduced in the vessels transduced with dnIKK beta. The present study reveals a previously unrecognized vascular response to angioplastic injury, characterized by NF-kappa B-dependent expression of NGAL in vascular SMCs. Furthermore, SMC-produced NGAL interacts with MMP-9, a mechanism by which NGAL may modulate MMP-9 proteolytic activity in the vascular repair process.