Chilukoti Ravi Kumar, Mostertz Jörg, Bukowska Alicja, Aderkast Christoph, Felix Stephan B, Busch Matthias, Völker Uwe, Goette Andreas, Wolke Carmen, Homuth Georg, Lendeckel Uwe
University Medicine, Ernst-Moritz-Arndt-University Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Greifswald, Germany.
Int J Cardiol. 2013 Oct 3;168(3):2100-8. doi: 10.1016/j.ijcard.2013.01.007. Epub 2013 Feb 12.
Atrial fibrillation (AF) is characterized by electrical and structural remodeling of the atria with atrial fibrosis being one hallmark. Angiotensin II (AngII) is a major contributing factor and blockage of its type I receptor (AT1R) prevents remodeling to some extent. Here we explored the effects of the AT1R antagonist irbesartan on global gene expression and profibrotic signaling pathways after induction of rapid atrial pacing (RAP) in vivo in pigs.
Microarray-based RNA profiling was used to screen left atrial (LA) tissue specimens for differences in atrial gene expression in a model of acute RAP. RAP caused an overall expression profile that reflected AngII-induced ROS production, tissue remodeling, and energy depletion. Of special note, the mRNA levels of EDN1, SGK1, and CTGF encoding pro-endothelin, stress- and glucocorticoid activated kinase-1, and of connective tissue growth factor were identified to be significantly increased after 7h of rapid pacing. These specific expression changes were additionally validated by RT-qPCR or immunoblot analyses in LA, RA, and partly in LV samples. All RAP-induced differential gene expression patterns were partially attenuated in the presence of irbesartan. Similar results were obtained after RAP of HL-1 cardiomyocytes in vitro. Furthermore, exogenously added endothelin-1 (ET1) induced CTGF expression concomitant to the transcriptional activation of SGK1 in HL-1 cells.
RAP provokes substantial changes in atrial and ventricular myocardial gene expression that could be partly reversed by irbesartan. ET1 contributes to AF-dependent atrial fibrosis by synergistic activity with AngII to stimulate SGK1 expression and enhance phosphorylation of the SGK1 protein which, in turn, induces CTGF. The latter has been consistently associated with tissue fibrosis. These findings suggest ETR antagonists as being beneficial in AF treatment.
心房颤动（AF）的特征是心房发生电重构和结构重构，心房纤维化是其中一个标志。血管紧张素II（AngII）是主要促成因素，阻断其I型受体（AT1R）可在一定程度上防止重构。在此，我们探讨了AT1R拮抗剂厄贝沙坦对猪体内快速心房起搏（RAP）诱导后全局基因表达和促纤维化信号通路的影响。
基于微阵列的RNA分析用于筛选急性RAP模型中左心房（LA）组织标本心房基因表达的差异。RAP导致整体表达谱反映了AngII诱导的活性氧生成、组织重构和能量消耗。特别值得注意的是，快速起搏7小时后，编码前内皮素、应激和糖皮质激素激活激酶-1的EDN1、SGK1以及结缔组织生长因子CTGF的mRNA水平显著升高。这些特定的表达变化在LA、RA以及部分LV样本中通过RT-qPCR或免疫印迹分析得到了进一步验证。在存在厄贝沙坦的情况下，所有RAP诱导的差异基因表达模式均部分减弱。体外对HL-1心肌细胞进行RAP后也得到了类似结果。此外，在HL-1细胞中外源性添加内皮素-1（ET1）可诱导CTGF表达，并伴随SGK1的转录激活。
RAP引发心房和心室心肌基因表达的大量变化，厄贝沙坦可部分逆转这些变化。ET1通过与AngII协同作用刺激SGK1表达并增强SGK1蛋白的磷酸化，进而诱导CTGF，从而导致AF相关的心房纤维化。后者一直与组织纤维化相关。这些发现表明内皮素受体拮抗剂在AF治疗中有益。
