LPS regulate ERK1/2-dependent signaling in cardiac fibroblasts via PKC-mediated MKP-1 induction
LPS regulate ERK1/2-dependent signaling in cardiac fibroblasts via PKC-mediated MKP-1 induction
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DOI：
10.1016/s0006-291x(03)00301-2
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发表时间：
2003-03-28
影响因子：
3.1
通讯作者：
Graf, K
中科院分区：
文献类型：
--
作者：
Stawowy, P;Goetze, S;Graf, K
血管紧张素II(Ang II)激活MAPK通路对心脏成纤维细胞(CFB)的增殖和迁移具有重要作用。MAP-K的活性受一组双特异性MAP-KP的密切控制。心力衰竭患者体内脂多糖(LPS)和细胞因子升高，可能导致疾病进展。本研究旨在探讨内毒素对血管紧张素Ⅱ诱导的CFB功能的影响。内毒素(1µg/mL，30min)可几乎完全抑制血管紧张素Ⅱ诱导的DNA合成，抑制血管紧张素Ⅱ的定向趋化作用达80%以上。与对照组相比，内毒素预处理显著降低ERK1/2-和p38MAPK的磷酸化水平，并诱导MKP-1的表达。用反义寡核苷酸沉默MKP-1可逆转内毒素对血管紧张素Ⅱ诱导的CFB DNA合成和迁移的抗致突变作用。蛋白激酶C(PKC)抑制剂Calphostin C可抑制脂多糖诱导的MKP-1，而ERK1/2途径抑制剂PD98059不能抑制其作用，提示脂多糖介导的CFBS中MKP-1的诱导需要PKC而不是ERK1/2。我们的数据表明，内毒素通过PKC介导的MKP-1诱导抑制血管紧张素转换酶II诱导的MAPK活性，从而对CFBS产生直接的细胞效应。这可能与人类慢性心力衰竭期间MAPK活性降低和MKPs水平升高有关。(C)2003年埃尔塞维尔科学公司(美国)。版权所有。
Activation of MAPK pathways by angiotensin II (Ang II) is important for cardiac fibroblast (CFB) proliferation and migration. Activity of MAP-kinases is closely controlled by a group of dual-specific MAP kinase phosphatases (MKPs). Lipopolysaccharides (LPS) and cytokines are elevated in patients with heart failure and may contribute to disease progression. In this study, we investigate the effect of LPS on Ang II-induced CFB function. Pretreatment of CFBs with LPS (1 mug/mL; 30 min) almost completely inhibited Ang II-induced DNA-synthesis and inhibited Ang II directed chemotaxis by more than 80%. Compared to controls, LPS pretreatment significantly reduced phosphorylation levels of ERK1/2- and p38 MAPK and induced MKP-1 levels. Silencing MKP-1 with antisense oligodesoxynucleotides reversed the antimitogenic effect of LPS on Ang II-induced CFB DNA-synthesis and migration. Induction of MKP-1 by LPS was inhibited by the protein kinase C (PKC)-inhibitor calphostin C, but not by the ERK1/2-pathway inhibitor PD98059, suggesting that PKC but not ERK1/2 is required for LPS-mediated MKP-1 induction in CFBs. Our data demonstrate that LPS have direct cellular effects in CFBs through an inhibition of Ang II-induced MAPK activity via PKC-mediated induction of MKP-1. This might be relevant with regard to the decreased MAPK activity and increased levels in MKPs reported during chronic heart failure in humans. (C) 2003 Elsevier Science (USA). All rights reserved.