Schmidt Constanze, Wiedmann Felix, Kallenberger Stefan M, Ratte Antonius, Schulte Jan S, Scholz Beatrix, Müller Frank Ulrich, Voigt Niels, Zafeiriou Maria-Patapia, Ehrlich Joachim R, Tochtermann Ursula, Veres Gábor, Ruhparwar Arjang, Karck Matthias, Katus Hugo A, Thomas Dierk
Department of Cardiology, University of Heidelberg, Heidelberg, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg / Mannheim, University of Heidelberg, Germany.
Department for Bioinformatics and Functional Genomics, Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg, Germany.
Prog Biophys Mol Biol. 2017 Nov;130(Pt B):233-243. doi: 10.1016/j.pbiomolbio.2017.05.004. Epub 2017 May 16.
Two-pore-domain potassium (K) channels modulate cellular excitability. The significance of stretch-activated cardiac K channels (K2.1, TREK-1, KCNK2; K4.1, TRAAK, KCNK4; K10.1, TREK-2, KCNK10) in heart disease has not been elucidated in detail. The aim of this work was to assess expression and remodeling of mechanosensitive K channels in atrial fibrillation (AF) and heart failure (HF) patients in comparison to murine models. Cardiac K channel levels were quantified in atrial (A) and ventricular (V) tissue obtained from patients undergoing open heart surgery. In addition, control mice and mouse models of AF (cAMP-response element modulator (CREM)-IbΔC-X transgenic animals) or HF (cardiac dysfunction induced by transverse aortic constriction, TAC) were employed. Human and murine KCNK2 displayed highest mRNA abundance among mechanosensitive members of the K channel family (V > A). Disease-associated K2.1 remodeling was studied in detail. In patients with impaired left ventricular function, atrial KCNK2 (K2.1) mRNA and protein expression was significantly reduced. In AF subjects, downregulation of atrial and ventricular KCNK2 (K2.1) mRNA and protein levels was observed. AF-associated suppression of atrial Kcnk2 (K2.1) mRNA and protein was recapitulated in CREM-transgenic mice. Ventricular Kcnk2 expression was not significantly altered in mouse models of disease. In conclusion, mechanosensitive K2.1 and K10.1 K channels are expressed throughout the heart. HF- and AF-associated downregulation of KCNK2 (K2.1) mRNA and protein levels suggest a mechanistic contribution to cardiac arrhythmogenesis.
双孔结构域钾（K）通道调节细胞兴奋性。牵张激活的心脏K通道（K2.1、TREK-1、KCNK2；K4.1、TRAAK、KCNK4；K10.1、TREK-2、KCNK10）在心脏病中的意义尚未得到详细阐明。本研究的目的是评估与小鼠模型相比，心房颤动（AF）和心力衰竭（HF）患者中机械敏感性K通道的表达和重塑情况。对接受心脏直视手术患者的心房（A）和心室（V）组织中的心脏K通道水平进行定量分析。此外，还使用了对照小鼠以及AF（环磷酸腺苷反应元件调节剂（CREM）-IbΔC-X转基因动物）或HF（经主动脉缩窄（TAC）诱导的心脏功能障碍）小鼠模型。在K通道家族的机械敏感性成员中，人和小鼠的KCNK2显示出最高的mRNA丰度（V > A）。对与疾病相关的K2.1重塑进行了详细研究。在左心室功能受损的患者中，心房KCNK2（K2.1）的mRNA和蛋白表达显著降低。在AF患者中，观察到心房和心室KCNK2（K2.1）的mRNA和蛋白水平下调。在CREM转基因小鼠中重现了AF相关的心房Kcnk2（K2.1）mRNA和蛋白的抑制情况。在疾病小鼠模型中，心室Kcnk2的表达没有显著改变。总之，机械敏感性K2.
