Briggs Laura E, Takeda Morihiko, Cuadra Adolfo E, Wakimoto Hiroko, Marks Melissa H, Walker Alexandra J, Seki Tsugio, Oh Suk P, Lu Jonathan T, Sumners Colin, Raizada Mohan K, Horikoshi Nobuo, Weinberg Ellen O, Yasui Kenji, Ikeda Yasuhiro, Chien Kenneth R, Kasahara Hideko
University of Florida College of Medicine, 1600 SW Archer Rd, M-540, Gainesville, FL 32610-0274, USA.
Circ Res. 2008 Sep 12;103(6):580-90. doi: 10.1161/CIRCRESAHA.108.171835. Epub 2008 Aug 8.
Homeobox transcription factor Nkx2-5, highly expressed in heart, is a critical factor during early embryonic cardiac development. In this study, using tamoxifen-inducible Nkx2-5 knockout mice, we demonstrate the role of Nkx2-5 in conduction and contraction in neonates within 4 days after perinatal tamoxifen injection. Conduction defect was accompanied by reduction in ventricular expression of the cardiac voltage-gated Na+ channel pore-forming alpha-subunit (Na(v)1.5-alpha), the largest ion channel in the heart responsive for rapid depolarization of the action potential, which leads to increased intracellular Ca2+ for contraction (conduction-contraction coupling). In addition, expression of ryanodine receptor 2, through which Ca2+ is released from sarcoplasmic reticulum, was substantially reduced in Nkx2-5 knockout mice. These results indicate that Nkx2-5 function is critical not only during cardiac development but also in perinatal hearts, by regulating expression of several important gene products involved in conduction and contraction.
同源框转录因子Nkx2-5在心脏中高度表达，是胚胎早期心脏发育过程中的关键因子。在本研究中，我们使用他莫昔芬诱导的Nkx2-5基因敲除小鼠，证明了Nkx2-5在围产期注射他莫昔芬后4天内对新生小鼠传导和收缩的作用。传导缺陷伴随着心脏电压门控性Na+通道孔形成α亚基（Na(v)1.5-α）心室表达的降低，Na(v)1.5-α是心脏中最大的离子通道，负责动作电位的快速去极化，进而导致细胞内Ca2+增加以促进收缩（传导-收缩偶联）。此外，Nkx2-5基因敲除小鼠中，通过其从肌浆网释放Ca2+的兰尼碱受体2的表达显著降低。这些结果表明，Nkx2-5不仅在心脏发育过程中起关键作用，在围产期心脏中也通过调节参与传导和收缩的几种重要基因产物的表达起关键作用。
