Csx/Nkx2-5 is required for homeostasis and survival of cardiac myocytes in the adult heart.
Csx/Nkx2-5, which is essential for cardiac development of the embryo, is abundantly expressed in the adult heart. We here examined the role of Csx/Nkx2-5 in the adult heart using two kinds of transgenic mice. Transgenic mice that overexpress a dominant negative mutant of Csx/Nkx2-5 (DN-TG mice) showed degeneration of cardiac myocytes and impairment of cardiac function. Doxorubicin induced more marked cardiac dysfunction in DN-TG mice and less in transgenic mice that overexpress wild type Csx/Nkx2-5 (WT-TG mice) compared with non-transgenic mice. Doxorubicin induced cardiomyocyte apoptosis, and the number of apoptotic cardiomyocytes was high in the order of DN-TG mice, non-transgenic mice, and WT-TG mice. Overexpression of the dominant negative mutant of Csx/Nkx2-5 induced apoptosis in cultured cardiomyocytes, while expression of wild type Csx/Nkx2-5 protected cardiomyocytes from doxorubicin-induced apoptotic death. These results suggest that Csx/Nkx2-5 plays a critical role in maintaining highly differentiated cardiac phenotype and in protecting the heart from stresses including doxorubicin.
Toko
Haruhiro
H
Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
Zhu
Weidong
W
Takimoto
Eiki
E
Shiojima
Ichiro
I
Hiroi
Yukio
Y
Zou
Yunzeng
Y
Oka
Toru
T
Akazawa
Hiroshi
H
Mizukami
Miho
M
Sakamoto
Masaya
M
Terasaki
Fumio
F
Kitaura
Yasushi
Y
Takano
Hiroyuki
H
Nagai
Toshio
T
Nagai
Ryozo
R
Komuro
Issei
I
D000818:Animals; D002470:Cell Survival / Q000502:physiology*; D017124:Conserved Sequence; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007930:Leucine; D051379:Mice; D008822:Mice, Transgenic; D016296:Mutagenesis; D009206:Myocardium / Q000166:cytology*; D011994:Recombinant Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D029867:Xenopus Proteins
D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; C484469:Nkx2-5 protein, mouse; D011994:Recombinant Proteins; D014157:Transcription Factors; D029867:Xenopus Proteins; D007930:Leucine