Palmitate induces C-reactive protein expression in human aortic endothelial cells. Relevance to fatty acid-induced endothelial dysfunction
Palmitate induces C-reactive protein expression in human aortic endothelial cells. Relevance to fatty acid-induced endothelial dysfunction
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DOI：
10.1016/j.metabol.2010.06.014
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发表时间：
2011-05-01
影响因子：
9.8
通讯作者：
Renier, Genevieve
中科院分区：
文献类型：
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作者：
Mugabo, Yves;Mukaneza, Yvette;Renier, Genevieve
代谢综合征患者的循环游离脂肪酸水平通常升高，并通过激活促炎途径对血管内皮产生有害影响。在这项研究中，我们研究了棕榈酸酯（PA）对内皮细胞C反应蛋白（CRP）表达的影响和CRP在PA诱导的一氧化氮（NO）抑制中的作用。棕榈酸以剂量依赖性方式增加人主动脉内皮细胞（HAECs）中CRP蛋白的表达和产生。神经酰胺模拟CRP蛋白的诱导，而溴棕榈酸和其他常见的游离脂肪酸，如油酸或亚油酸是无效的。棕榈酸还引起HAECs中活性氧的产生，这种作用可被蛋白激酶C（PKC）抑制和腺苷一磷酸激活的激酶（AMPK）激活所阻止。棕榈酸处理的HAEC显示CRP信使RNA表达增加和核因子（NF）-κ B活化。抗氧化剂可阻止PA诱导的CRP表达，PKC和丝裂原活化蛋白激酶抑制剂可使其正常化。破坏NF-κ B和Janus激酶/信号转导和转录途径的激活物或诱导AMPK激活也抑制PA对CRP信使RNA表达的刺激作用。最后，在HAECs中，PA减少NO释放，抗CRP抗体逆转了这种作用。这些数据表明，PA诱导的内皮CRP表达涉及PKC驱动的氧化应激，可能通过AMPK抑制和下游氧化还原敏感性信号通路的激活，包括NF-κ B。它们进一步支持内皮细胞衍生的CRP作为PA对NO产生的抑制作用的介体的作用。(C)2011 Elsevier Inc. All rights reserved.
Circulating levels of free fatty acids are commonly elevated in patients with the metabolic syndrome and exert, through activating proinflammatory pathways, harmful effects of the vascular endothelium. In this study, we examined the effect of palmitate (PA) on endothelial C-reactive protein (CRP) expression and the role of CRP in PA-induced nitric oxide (NO) inhibition. Palmitate increased, in a dose-dependent manner, CRP protein expression and production in human aortic endothelial cells (HAECs). Induction of CRP protein was mimicked by ceramide, whereas bromopalmitate and other common free fatty acids such as oleate or linoleate were ineffective. Palmitate also elicited reactive oxygen species production in HAECs, an effect prevented by protein kinase C (PKC) inhibition and adenosine monophosphate activated kinase (AMPK) activation. Palmitate-treated HAECs showed increased CRP messenger RNA expression and nuclear factor (NF)-kappa B activation. Induction of CRP expression by PA was prevented by antioxidants and normalized by PKC and mitogen-activated protein kinase inhibitors. Disrupting NF-kappa B and Janus kinase/signal transducers and activators of transcription pathways or inducing AMPK activation also suppressed the stimulatory effect of PA on CRP messenger RNA expression. Finally, in HAECs, PA reduced NO release, an effect reversed by anti-CRP antibody. These data demonstrate that PA-induced endothelial CRP expression involves PKC-driven oxidative stress, possibly through AMPK inhibition, and activation of downstream redox-sensitive signaling pathways, including NF-kappa B. They further support a role for endothelial cell derived CRP as mediator of the suppressive effect of PA on NO production. (C) 2011 Elsevier Inc. All rights reserved.