Endothelin-1 Promotes Cardiomyocyte Terminal Differentiation in the Developing Heart Via Heightened DNA Methylation

Overview

Journal Int J Med Sci

Specialty General Medicine

Date 2014 Mar 1

PMID 24578615

Citations 16

Authors

Alexandra Paradis

Daliao Xiao

Jianjun Zhou

Lubo Zhang

Affiliations

Soon will be listed here.

Abstract

Aims: 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.

Methods And Results: Hypoxia (10.5% O2) treatment of pregnant rats from day 15 to day 21 resulted in a significant increase in prepro-ET-1 mRNA expression in fetal hearts. ET-1 ex vivo treatment of fetal rat cardiomyocytes increased percent binucleate cells and decreased Ki-67 expression, a marker for proliferation, under both control and hypoxic conditions. Hypoxia alone decreased Ki-67 expression and in conjunction with ET-1 treatment decreased cardiomyocyte size. PD145065, a non-selective ET-receptor antagonist, blocked the changes in binucleation and proliferation caused by ET-1. DNA methylation in fetal cardiomyocytes was significantly increased with ET-1 treatment, which was 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.

Conclusions: 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.

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References

Drimal J, Knezl V, Drimal Jr J, Drimal D, Bauerova K, Kettmann V . Cardiac effects of endothelin-1 (ET-1) and related C terminal peptide fragment: increased inotropy or contribution to heart failure?. Physiol Res. 2003; 52(6):701-8. View

Kedzierski R, Yanagisawa M . Endothelin system: the double-edged sword in health and disease. Annu Rev Pharmacol Toxicol. 2001; 41:851-76. DOI: 10.1146/annurev.pharmtox.41.1.851. View

Tong W, Xue Q, Li Y, Zhang L . Maternal hypoxia alters matrix metalloproteinase expression patterns and causes cardiac remodeling in fetal and neonatal rats. Am J Physiol Heart Circ Physiol. 2011; 301(5):H2113-21. PMC: 3213965. DOI: 10.1152/ajpheart.00356.2011. View

Ceccarelli F, Scavuzzo M, Giusti L, Bigini G, Costa B, Carnicelli V . ETA receptor-mediated Ca2+ mobilisation in H9c2 cardiac cells. Biochem Pharmacol. 2003; 65(5):783-93. DOI: 10.1016/s0006-2952(02)01624-6. View

George E, Granger J . Endothelin: key mediator of hypertension in preeclampsia. Am J Hypertens. 2011; 24(9):964-9. PMC: 3388717. DOI: 10.1038/ajh.2011.99. View

Kohan D, Rossi N, Inscho E, Pollock D . Regulation of blood pressure and salt homeostasis by endothelin. Physiol Rev. 2011; 91(1):1-77. PMC: 3236687. DOI: 10.1152/physrev.00060.2009. View

Li F, Wang X, Capasso J, Gerdes A . Rapid transition of cardiac myocytes from hyperplasia to hypertrophy during postnatal development. J Mol Cell Cardiol. 1996; 28(8):1737-46. DOI: 10.1006/jmcc.1996.0163. View

Thaete L, Jilling T, Synowiec S, Khan S, Neerhof M . Expression of endothelin 1 and its receptors in the hypoxic pregnant rat. Biol Reprod. 2007; 77(3):526-32. PMC: 1989130. DOI: 10.1095/biolreprod.107.061820. View

Li H, Chen S, Chen Y, Meng Q, Durand J, Oparil S . Enhanced endothelin-1 and endothelin receptor gene expression in chronic hypoxia. J Appl Physiol (1985). 1994; 77(3):1451-9. DOI: 10.1152/jappl.1994.77.3.1451. View

10.

Tong W, Zhang L . Fetal hypoxia and programming of matrix metalloproteinases. Drug Discov Today. 2011; 17(3-4):124-34. PMC: 3248990. DOI: 10.1016/j.drudis.2011.09.011. View

11.

Xiong F, Xiao D, Zhang L . Norepinephrine causes epigenetic repression of PKCε gene in rodent hearts by activating Nox1-dependent reactive oxygen species production. FASEB J. 2012; 26(7):2753-63. PMC: 3382091. DOI: 10.1096/fj.11-199422. View

12.

Hammoud L, Xiang F, Lu X, Brunner F, Leco K, Feng Q . Endothelial nitric oxide synthase promotes neonatal cardiomyocyte proliferation by inhibiting tissue inhibitor of metalloproteinase-3 expression. Cardiovasc Res. 2007; 75(2):359-68. DOI: 10.1016/j.cardiores.2007.05.006. View

13.

Patterson A, Chen M, Xue Q, Xiao D, Zhang L . Chronic prenatal hypoxia induces epigenetic programming of PKC{epsilon} gene repression in rat hearts. Circ Res. 2010; 107(3):365-73. PMC: 2919213. DOI: 10.1161/CIRCRESAHA.110.221259. View

14.

Xu Y, Williams S, OBrien D, Davidge S . Hypoxia or nutrient restriction during pregnancy in rats leads to progressive cardiac remodeling and impairs postischemic recovery in adult male offspring. FASEB J. 2006; 20(8):1251-3. DOI: 10.1096/fj.05-4917fje. View

15.

Chen H, Yu S, Chen W, Yang P, Chien C, Chou H . Dynamic changes of gene expression profiles during postnatal development of the heart in mice. Heart. 2004; 90(8):927-34. PMC: 1768375. DOI: 10.1136/hrt.2002.006734. View

16.

Yu L, Li M, She T, Shi C, Meng W, Wang B . Endothelin-1 stimulates the expression of L-type Ca2+ channels in neonatal rat cardiomyocytes via the extracellular signal-regulated kinase 1/2 pathway. J Membr Biol. 2013; 246(4):343-53. DOI: 10.1007/s00232-013-9538-7. View

17.

Zolk O, Quattek J, Sitzler G, Schrader T, Nickenig G, Schnabel P . Expression of endothelin-1, endothelin-converting enzyme, and endothelin receptors in chronic heart failure. Circulation. 1999; 99(16):2118-23. DOI: 10.1161/01.cir.99.16.2118. View

18.

Liu Y, Tang M, Cai D, Li M, Wong W, Chow P . Cyclin I and p53 are differentially expressed during the terminal differentiation of the postnatal mouse heart. Proteomics. 2006; 7(1):23-32. DOI: 10.1002/pmic.200600456. View

19.

Botting K, Wang K, Padhee M, McMillen I, Summers-Pearce B, Rattanatray L . Early origins of heart disease: low birth weight and determinants of cardiomyocyte endowment. Clin Exp Pharmacol Physiol. 2011; 39(9):814-23. DOI: 10.1111/j.1440-1681.2011.05649.x. View

20.

Yamashita K, Discher D, Hu J, Bishopric N, Webster K . Molecular regulation of the endothelin-1 gene by hypoxia. Contributions of hypoxia-inducible factor-1, activator protein-1, GATA-2, AND p300/CBP. J Biol Chem. 2001; 276(16):12645-53. DOI: 10.1074/jbc.M011344200. View