Key result
Overexpression of wild type Csx/Nkx2-5 protected cardiomyocytes from doxorubicin-induced apoptosis, whereas a dominant negative mutant induced degeneration and exacerbated cardiac dysfunction.
Csx/Nkx2-5 plays a critical role in maintaining the adult cardiac phenotype and protecting cardiomyocytes from stress such as doxorubicin.
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May support Csx/Nkx2-5 as a stress-response factor in animal models; leaves open human translation and therapeutic targeting.
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.
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Toko et al. (2002) studied Doxorubicin-induced cardiac dysfunction and apoptosis. Overexpression of wild type or dominant negative mutant Csx/Nkx2-5 vs. Non-transgenic mice and control cardiomyocytes was evaluated on Cardiac dysfunction and cardiomyocyte apoptosis. Overexpression of wild type Csx/Nkx2-5 protected cardiomyocytes from doxorubicin-induced apoptosis, whereas a dominant negative mutant induced degeneration and exacerbated cardiac dysfunction.
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