Signaling pathways involved in OxPAPC-induced pulmonary endothelial barrier protection
Signaling pathways involved in OxPAPC-induced pulmonary endothelial barrier protection
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DOI：
10.1016/j.mvr.2006.12.004
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发表时间：
2007-05-01
影响因子：
3.1
通讯作者：
Birukov, Konstantin G.
中科院分区：
文献类型：
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作者：
Birukova, Anna A.;Chatchavalvanich, Santipongse;Birukov, Konstantin G.
已在多种慢性和急性病理状况中检测到氧化磷脂的组织或血清水平增加，所述慢性和急性病理状况例如高脂血症、动脉粥样硬化、心脏病发作、细胞凋亡、急性炎症和损伤。我们最近描述了由氧化的1-棕榈酰-2-花生四烯酸-sn-甘油-3-磷酸胆碱（OxPAPC）在人肺动脉内皮细胞（EC）中激活的信号级联，并报道了OxPAPC的有效屏障保护作用，其由小GTP酶Rac和Cdc 42介导。在这项研究中，我们进一步表征了参与OxPAPC介导的内皮屏障保护的信号传导途径。小GTP酶、蛋白激酶A（PKA）、蛋白激酶C（PKC）、Src家族激酶的抑制剂和酪氨酸激酶的一般抑制剂减弱OxPAPC诱导的屏障保护反应和EC细胞骨架重塑。而小G T β Rho、Rho激酶、Erk-1，2 MAP激酶、p38 MAP激酶和PI 3-激酶不参与OxPAPC的屏障保护作用。PKA、PKC、酪氨酸激酶抑制剂和小G蛋白激酶抑制剂毒素B抑制OxPAPC诱导的Rac活化，并降低粘着斑激酶（FAK）和桩蛋白的磷酸化。OxPAPC的屏障保护作用不能被血小板活化因子（PAF）复制，PAF在高浓度下诱导屏障功能障碍，但被PAF受体拮抗剂A85783部分减弱。这些结果首次证实了上游信号级联参与OxPAPC诱导的Rae激活、细胞骨架重塑和屏障调节，并表明OxPAPC介导的内皮屏障保护的PAF受体非依赖性机制。(C)2007年爱思唯尔公司All rights reserved.
Increased tissue or serum levels of oxidized phospholipids have been detected in a variety of chronic and acute pathological conditions such as hyperlipidemia, atherosclerosis, heart attack, cell apoptosis, acute inflammation and injury. We have recently described signaling cascades activated by oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC)in the human pulmonary artery endothelial cells (EC) and reported potent barrier-protective effects of OxPAPC, which were mediated by small GTPases Rac and Cdc42. In this study we have further characterized signal transduction pathways involved in the OxPAPC-mediated endothelial barrier protection. Inhibitors of small GTPases, protein kinase A (PKA), protein kinase C (PKC), Src family kinases and general inhibitors of tyrosine kinases attenuated OxPAPC-induced barrier- protective response and EC cytoskeletal remodeling. In contrast, small GTPase Rho, Rho kinase, Erk-1,2 MAP kinase and p38 MAP kinase and PI3-kinase were not involved in the barrier-protective effects of OxPAPC. Inhibitors of PKA, PKC, tyrosine kinases and small GTPase inhibitor toxin B suppressed OxPAPC-induced Rac activation and decreased phosphorylation of focal adhesion kinase (FAK) and paxillin. Barrier-protective effects of OxPAPC were not reproduced by platelet activating factor (PAF), which at high concentrations induced barrier dysfunction, but were partially attenuated by PAF receptor antagonist A85783. These results demonstrate for the first time upstream signaling cascades involved in the OxPAPC-induced Rae activation, cytoskeletal remodeling and barrier regulation and suggest PAF receptor-independent mechanisms of OxPAPC-mediated endothelial barrier protection. (C) 2007 Elsevier Inc. All rights reserved.