Department of Cellular Physiology and Signal Transduction, Sapporo Medical University School of Medicine, Sapporo, Japan;
Am J Physiol Heart Circ Physiol. 2014 Apr 1;306(7):H1054-65. doi: 10.1152/ajpheart.00414.2013. Epub 2014 Jan 31.
In the present study, we examined if and how cardiac ion channels are modified by type 2 diabetes mellitus (T2DM). Subendocardial (Endo) myocytes and subepicardial (Epi) myocytes were isolated from left ventricles of Otsuka-Long-Evans-Tokushima Fatty rats (OLETF) rats, a rat model of T2DM, and Otsuka-Long-Evans-Tokushima (LETO) rats (nondiabetic control rats). Endo and Epi myocytes were used for whole cell patch-clamp recordings and for protein and mRNA analyses. Action potential durations in Endo and Epi myocytes were longer in OLETF rats than in LETO rats, and the difference was larger in Endo myocytes. Steady-state transient outward K+ current (Ito) density was reduced in Endo but not Epi myocytes of OLETF rats compared with LETO rats, although the contribution of the fast component of Ito recovery from inactivation was smaller in both Endo and Epi myocytes of OLETF rats than in LETO rats. Kv4.2 protein was reduced only in Endo myocytes in OLETF rats, although voltage-gated K+ channel-interacting protein 2 (KChIP2) protein levels in both Endo and Epi myocytes were lower in OLETF rats than in LETO rats. Corresponding regional differences in mRNA levels of KChIP2 and Kv4.2 were observed between OLETF and LETO rats. mRNA levels of Iroquois homeobox 5 in Endo myocytes were 53% higher in OLETF rats than in LETO rats. Densities of inward rectifier K+ current and L-type Ca2+ current and mRNA levels of Kv4.3 and Kv1.4 were similar in OLETF and LETO rats. In conclusion, T2DM induces Endo-predominant prolongation of the action potential duration via a reduction of the fast component of Ito recovery from inactivation and reduced steady-state Ito, in which downregulation of Kv4.2 and KChIP2 may be involved. Increased Iroquois homeobox 5 expression may underlie Kv4.2 downregulation in T2DM.
在本研究中，我们研究了 2 型糖尿病（T2DM）是否以及如何改变心脏离子通道。从 2 型糖尿病大鼠模型大冢龙-长野-富山肥胖大鼠（OLETF）和大冢龙-长野（LETO）大鼠的左心室分离出心内膜（Endo）和心外膜（Epi）心肌细胞。使用全细胞膜片钳记录和蛋白质及 mRNA 分析来研究 Endo 和 Epi 心肌细胞。与 LETO 大鼠相比，OLETF 大鼠的 Endo 和 Epi 心肌细胞的动作电位时程较长，而 Endo 心肌细胞的差异更大。与 LETO 大鼠相比，OLETF 大鼠的 Endo 心肌细胞而非 Epi 心肌细胞的稳态瞬间外向 K+电流（Ito）密度降低，尽管 Ito 从失活中快速恢复的快速成分在 OLETF 和 LETO 大鼠的 Endo 和 Epi 心肌细胞中都较小。只有 OLETF 大鼠的 Endo 心肌细胞中 Kv4.2 蛋白减少，尽管 OLETF 大鼠的 Endo 和 Epi 心肌细胞中电压门控 K+通道相互作用蛋白 2（KChIP2）蛋白水平低于 LETO 大鼠。在 OLETF 和 LETO 大鼠之间观察到 KChIP2 和 Kv4.2 的相应区域差异mRNA 水平。Endo 心肌细胞中 Iroquois 同源盒 5 的 mRNA 水平在 OLETF 大鼠中比 LETO 大鼠高 53%。内向整流钾电流和 L 型钙电流的密度以及 Kv4.3 和 Kv1.4 的 mRNA 水平在 OLETF 和 LETO 大鼠中相似。总之，T2DM 通过减少 Ito 从失活中快速恢复的成分和降低稳态 Ito 来引起 Endo 为主的动作电位时程延长，其中 Kv4.2 和 KChIP2 的下调可能涉及其中。Iroquois 同源盒 5 表达的增加可能是 T2DM 中 Kv4.2 下调的基础。
