Naumenko Nikolay, Huusko Jenni, Tuomainen Tomi, Koivumäki Jussi T, Merentie Mari, Gurzeler Erika, Alitalo Kari, Kivelä Riikka, Ylä-Herttuala Seppo, Tavi Pasi
A.I. Virtanen Institute for Molecular Sciences, University of Eastern FinlandKuopio, Finland.
Wihuri Research Institute and Translational Cancer Biology Program, University of Helsinki, Biomedicum HelsinkiHelsinki, Finland.
Front Physiol. 2017 May 31;8:373. doi: 10.3389/fphys.2017.00373. eCollection 2017.
Vascular endothelial growth factor B (VEGF-B) is a potent mediator of vascular, metabolic, growth, and stress responses in the heart, but the effects on cardiac muscle and cardiomyocyte function are not known. The purpose of this study was to assess the effects of VEGF-B on the energy metabolism, contractile, and electrophysiological properties of mouse cardiac muscle and cardiac muscle cells. and analysis of cardiac-specific VEGF-B TG mice indicated that the contractile function of the TG hearts was normal. Neither the oxidative metabolism of isolated TG cardiomyocytes nor their energy substrate preference showed any difference to WT cardiomyocytes. Similarly, myocyte Ca signaling showed only minor changes compared to WT myocytes. However, VEGF-B overexpression induced a distinct electrophysiological phenotype characterized by ECG changes such as an increase in QRSp time and decreases in S and R amplitudes. At the level of isolated TG cardiomyocytes, these changes were accompanied with decreased action potential upstroke velocity and increased duration (APD). These changes were partly caused by downregulation of sodium current (I) due to reduced expression of Na1.5. Furthermore, TG myocytes had alterations in voltage-gated K currents, namely decreased density of transient outward current (I) and total K current (I). At the level of transcription, these were accompanied by downregulation of K channel-interacting protein 2 (), a known modulatory subunit for K4.2/3 channel. Cardiac VEGF-B overexpression induces a distinct electrophysiological phenotype including remodeling of cardiomyocyte ion currents, which in turn induce changes in action potential waveform and ECG.
血管内皮生长因子B（VEGF - B）是心脏血管、代谢、生长及应激反应的强效介质，但对心肌和心肌细胞功能的影响尚不清楚。本研究旨在评估VEGF - B对小鼠心肌和心肌细胞能量代谢、收缩及电生理特性的影响。对心脏特异性VEGF - B转基因（TG）小鼠的分析表明，TG心脏的收缩功能正常。分离的TG心肌细胞的氧化代谢及其能量底物偏好与野生型（WT）心肌细胞均无差异。同样，与WT心肌细胞相比，心肌细胞钙信号仅显示出微小变化。然而，VEGF - B过表达诱导了一种独特的电生理表型，其特征为心电图变化，如QRSp时间增加、S波和R波振幅降低。在分离的TG心肌细胞水平，这些变化伴随着动作电位上升速度降低和时程（APD）增加。这些变化部分是由于Na1.5表达减少导致钠电流（I）下调所致。此外，TG心肌细胞的电压门控钾电流发生改变，即瞬时外向电流（I）密度和总钾电流（I）降低。在转录水平，这些变化伴随着钾通道相互作用蛋白2（）下调，该蛋白是K4.2/3通道的已知调节亚基。心脏VEGF - B过表达诱导了一种独特的电生理表型，包括心肌细胞离子电流重塑，进而引起动作电位波形和心电图变化。
