Nkx2.5 homeoprotein regulates expression of gap junction protein connexin 43 and sarcomere organization in postnatal cardiomyocytes
Nkx2.5 homeoprotein regulates expression of gap junction protein connexin 43 and sarcomere organization in postnatal cardiomyocytes
复制标题
DOI：
10.1016/s0022-2828(03)00002-6
复制
发表时间：
2003-03-01
影响因子：
5
通讯作者：
Izumo, S
中科院分区：
文献类型：
--
作者：
Kasahara, H;Ueyama, T;Izumo, S
Nkx2.5是一种进化上保守的含有转录因子的同源域，是最早的心源性标记物之一。尽管其表达持续到成年期，但其在成年心肌细胞中的功能尚不清楚。为了检查 Nkx2.5 在终末分化的出生后心肌细胞中的作用，我们生成了在 a-肌球蛋白重链启动子下表达野生型 Nkx2.5 (TG-wild)、推定的转录活性突变体 (羧基末端缺失突变体：TG-DeltaC) 或 Nkx2.5 DNA 非结合点突变体 (TG-I183P) 的转基因小鼠。大多数 TG-wild 和 TG-DeltaC 小鼠在 4 个月龄前死于与传导异常相关的心力衰竭。表达野生型 Nkx2.5 或假定的转录活性突变体 (DeltaC) 的心肌细胞显着降低了连接蛋白 43 的表达并改变了肌节结构。野生型 Nkx2.5 腺病毒感染的成年心肌细胞早在感染后 16 小时就表现出连接蛋白 43 下调，表明连接蛋白 43 下调是由于 Nkx2.5 过度表达，而不是由于体内心力衰竭表型。这些研究表明，终末分化心肌细胞中 Nkx2.5 的过度表达会显着改变心脏细胞的结构和功能。 (C) 2003 Elsevier Science Ltd. 保留所有权利。
Nkx2.5, an evolutionarily conserved homeodomain containing transcription factor, is one of the earliest cardiogenic markers. Although its expression continues through adulthood, its function in adult cardiomyocytes is not well understood. To examine the effect of Nkx2.5 in terminal differentiated postnatal cardiomyocytes, we generated transgenic mice expressing either wild-type Nkx2.5 (TG-wild), a putative transcriptionally active mutant (carboxyl-terminus deletion mutant: TG-DeltaC) or a DNA non-binding point mutant of Nkx2.5 (TG-I183P) under a-myosin heavy chain promoter. Most TG-wild and TG-DeltaC mice died before 4 months of age with heart failure associated with conduction abnormalities. Cardiomyocytes expressing wild-type Nkx2.5 or a putative transcriptionally active mutant (DeltaC) had dramatically reduced expression of connexin 43 and changed sarcomere structure. Wild-type Nkx2.5 adenovirus-infected adult cardiomyocytes demonstrated connexin 43 downregulation as early as 16 h after infection, indicating that connexin 43 downregulation is due to Nkx2.5 overexpression but not due to heart failure phenotype in vivo. These studies indicate that overexpression of Nkx2.5 in terminally differentiated cardiomyocytes dramatically alters cardiac cell structure and function. (C) 2003 Elsevier Science Ltd. All rights reserved.