Kračun Damir, Riess Florian, Kanchev Ivan, Gawaz Meinrad, Görlach Agnes
1 Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, Technical University Munich , Munich, Germany.
Antioxid Redox Signal. 2014 May 1;20(13):1964-76. doi: 10.1089/ars.2013.5286. Epub 2014 Mar 13.
Integrins are multifunctional heterodimeric adhesion receptors that mediate the attachment between a cell and the extracellular matrix or other surrounding cells. In endothelial cells, integrins can modulate cell migration and motility. In particular, β3-integrin is expressed in angiogenic vessels. Signal transduction by β3-integrins requires the recruitment of intracellular signaling molecules. β3-endonexin is a highly spliced molecule that has been identified as a β3-integrin binding protein. β3-endonexin isoforms are expressed in endothelial cells and have been suggested to act as shuttle proteins between the membrane and the nucleus. However, their functional role in angiogenesis is unclear. In this study, we investigated whether β3-endonexin isoforms are involved in endothelial angiogenic processes under hypoxia.
The overexpression of β3-endonexin isoforms decreased endothelial proliferation and tube formation under hypoxia, while the depletion of β3-endonexin by RNAi promoted angiogenic responses in vitro and in vivo. In hypoxia, β3-endonexin accumulated in the nucleus, and prevention of this response by depletion of β3-endonexin increased hypoxic activation and induction of the hypoxia-inducible factor (HIF)-1 and its target genes VEGF and PAI-1. β3-endonexin diminished nuclear factor kappa B (NFκB) activation and decreased NFκB binding to the HIF-1α promoter under hypoxia, subsequently diminishing NFκB-dependent transcription of HIF-1α under hypoxia.
Our results indicate for the first time that the overexpression of β3-endonexin can decrease hypoxic induction and activation of HIF-1α and can prevent hypoxic endothelial proliferation and angiogenic responses.
β3-endonexin can act as a novel anti-angiogenic factor specifically in the response to hypoxia due to its negative impact on the activation of HIF-1.
整合素是多功能异二聚体黏附受体，介导细胞与细胞外基质或其他周围细胞之间的附着。在内皮细胞中，整合素可调节细胞迁移和运动性。特别是，β3整合素在血管生成血管中表达。β3整合素的信号转导需要募集细胞内信号分子。β3内毒素是一种高度剪接的分子，已被鉴定为β3整合素结合蛋白。β3内毒素异构体在内皮细胞中表达，并被认为可作为膜与细胞核之间的穿梭蛋白。然而，它们在血管生成中的功能作用尚不清楚。在本研究中，我们调查了β3内毒素异构体是否参与缺氧条件下的内皮血管生成过程。
β3内毒素异构体的过表达在缺氧条件下降低了内皮细胞增殖和管形成，而RNAi介导的β3内毒素缺失在体外和体内均促进了血管生成反应。在缺氧条件下，β3内毒素在细胞核中积累，通过缺失β3内毒素来阻止这种反应可增加缺氧诱导因子（HIF）-1及其靶基因VEGF和PAI-1的缺氧激活和诱导。β3内毒素在缺氧条件下减少核因子κB（NFκB）的激活，并降低NFκB与HIF-1α启动子的结合，随后减少缺氧条件下NFκB依赖的HIF-1α转录。
我们的结果首次表明，β3内毒素的过表达可降低缺氧诱导和HIF-1α的激活，并可阻止缺氧内皮细胞增殖和血管生成反应。
β3内毒素可作为一种新型抗血管生成因子，特别是在对缺氧的反应中，因为它对HIF-1的激活有负面影响。
