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Endothelin‐1 promotes fetal cardiomyocyte terminal differentiation via heightened DNA methylation (862.2)
Author(s) -
Paradis Alexandra,
Xiao Daliao,
Zhou Jianjun,
Zhang Lubo
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.862.2
Subject(s) - dna methylation , biology , fetus , medicine , endocrinology , endothelin 1 , methylation , hypoxia (environmental) , dna synthesis , cell growth , andrology , gene expression , receptor , dna , chemistry , pregnancy , biochemistry , gene , oxygen , genetics , organic chemistry
Hypoxia is a major stress on fetal development and leads to induction of endothelin‐1 (ET‐1) expression. We tested the hypothesis that ET‐1 stimulates the terminal differentiation of cardiomyocytes from mononucleate to binucleate in the developing heart. In fetal hearts, prepro‐ET‐1 mRNA expression was significantly increased by hypoxia (10.5% O2) treatment of pregnant rats from day 15 to day 21. Under both control and hypoxic conditions, the ET‐1 ex vivo treatment of fetal rat cardiomyocytes increased percent binucleate cells and decreased Ki‐67 expression, a proliferation marker. Hypoxia alone was able to decrease Ki‐67 expression and cardiomyocyte size. A non‐selective ET‐receptor antagonist, PD145065, blocked the ET‐1 induced changes in binucleation and proliferation. ET‐1 treatment significantly increased DNA methylation in fetal cardiomyocytes, which was further blocked by 5‐aza‐2’‐deoxycytidine, a DNA methylation inhibitor. In addition, 5‐aza‐2’‐deoxycytidine treatment abrogated the increase in binucleation and decrease in proliferation induced by ET‐1. Hypoxic stress and synthesis of ET‐1 increases DNA methylation and promotes terminal differentiation of cardiomyocytes in the developing heart. This premature exit of the cell cycle may lead to a reduced cardiomyocyte endowment in the heart and have a negative impact on cardiac function.