Bukowska Alicja, Schild Lorenz, Keilhoff Gerburg, Hirte Daniel, Neumann Manfred, Gardemann Andreas, Neumann Klaus Hinrich, Röhl Friedrich-Wilhelm, Huth Christof, Goette Andreas, Lendeckel Uwe
University Hospital Magdeburg, Institute of Experimental Internal Medicine, Leipzigerstrasse 44, 39120 Magdeburg, Germany.
Exp Biol Med (Maywood). 2008 May;233(5):558-74. doi: 10.3181/0706-RM-155. Epub 2008 Mar 28.
Accumulating evidence links calcium-overload and oxidative stress to atrial remodeling during atrial fibrillation (AF). Furthermore, atrial remodeling appears to increase atrial thrombogeneity, characterized by increased expression of adhesion molecules. The aim of this study was to assess mitochondrial dysfunction and oxidative stress-activated signal transduction (nuclear factor-kappaB [NF-kappa B], lectin-like oxidized low-density lipoprotein receptor [LOX-1], intercellular adhesion molecule-1 [ICAM-1], and hemeoxgenase-1 [HO-1]) in atrial tissue during AF. Ex vivo atrial tissue from patients with and without AF and, additionally, rapid pacing of human atrial tissue slices were used to study mitochondrial structure by electron microscopy and mitochondrial respiration. Furthermore, quantitative reverse transcription polymerase chain reaction (RT-PCR), immunoblot analyses, gel-shift assays, and enzyme-linked immunosorbent assay (ELISA) were applied to measure nuclear amounts of NF-kappa B target gene expression. Using ex vivo atrial tissue samples from patients with AF we demonstrated oxidative stress and impaired mitochondrial structure and respiration, which was accompanied by nuclear accumulation of NF-kappa B and elevated expression levels of the adhesion molecule ICAM-1 and the oxidative stress-induced markers HO-1 and LOX-1. All these changes were reproduced by rapid pacing for 24 hours of human atrial tissue slices. Furthermore, the blockade of calcium inward current with verapamil effectively prevented both the mitochondrial changes and the activation of NF-kappa B signaling and target gene expression. The latter appeared also diminished by the antioxidants apocynin and resveratrol (an inhibitor of NF-kappa B), or the angiotensin II receptor type 1 antagonist, olmesartan. This study demonstrates that calcium inward current via L-type calcium channels contributes to oxidative stress and increased expression of oxidative stress markers and adhesion molecules during cardiac tachyarrhythmia.
越来越多的证据表明，钙超载和氧化应激与心房颤动（AF）期间的心房重构有关。此外，心房重构似乎会增加心房血栓形成倾向，其特征是黏附分子表达增加。本研究的目的是评估AF期间心房组织中的线粒体功能障碍和氧化应激激活的信号转导（核因子-κB [NF-κB]、凝集素样氧化低密度脂蛋白受体[LOX-1]、细胞间黏附分子-1 [ICAM-1]和血红素加氧酶-1 [HO-1]）。使用有或无AF患者的离体心房组织，以及另外对人心房组织切片进行快速起搏，通过电子显微镜和线粒体呼吸来研究线粒体结构。此外，应用定量逆转录聚合酶链反应（RT-PCR）、免疫印迹分析、凝胶迁移分析和酶联免疫吸附测定（ELISA）来测量NF-κB靶基因表达的核量。使用AF患者的离体心房组织样本，我们证明了氧化应激以及线粒体结构和呼吸受损，同时伴有NF-κB的核积聚以及黏附分子ICAM-1和氧化应激诱导标志物HO-1和LOX-1的表达水平升高。所有这些变化在人心房组织切片快速起搏24小时后重现。此外，用维拉帕米阻断钙内流有效地预防了线粒体变化以及NF-κB信号传导和靶基因表达的激活。抗氧化剂阿朴吗啡和白藜芦醇（一种NF-κB抑制剂）或血管紧张素II 1型受体拮抗剂奥美沙坦似乎也能减轻后者。本研究表明，通过L型钙通道的钙内流在心脏快速性心律失常期间促成氧化应激以及氧化应激标志物和黏附分子表达增加。
