Abstract
Background:
Angiotensin II (ANG II) stimulates fetal heart growth, although little is known regarding changes in cardiomyocyte endowment or the molecular pathways mediating the response. We measured cardiomyocyte proliferation and morphology in ANG II–treated fetal sheep and assessed transcriptional pathway responses in ANG II and losartan (an ANG II type 1 receptor antagonist) treated fetuses.
Methods:
In twin-gestation pregnant sheep, one fetus received ANG II (50 μg/kg/min i.v.) or losartan (20 mg/kg/d i.v.) for 7 d; noninstrumented twins served as controls.
Results:
ANG II produced increases in heart mass, cardiomyocyte area (left ventricle (LV) and right ventricle mononucleated and LV binucleated cells), and the percentage of Ki-67–positive mononucleated cells in the LV (all P < 0.05). ANG II and losartan produced generally opposing changes in gene expression, affecting an estimated 55% of the represented transcriptome. The most prominent significantly affected biological pathways included those involved in cytoskeletal remodeling and cell cycle activity.
Conclusion:
ANG II produces an increase in fetal cardiac mass via cardiomyocyte hypertrophy and likely hyperplasia, involving transcriptional responses in cytoskeletal remodeling and cell cycle pathways.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Barry SP, Davidson SM, Townsend PA . Molecular regulation of cardiac hypertrophy. Int J Biochem Cell Biol 2008;40:2023–39.
Thornburg K, Jonker S, O’Tierney P, et al. Regulation of the cardiomyocyte population in the developing heart. Prog Biophys Mol Biol 2011;106:289–99.
Jonker SS, Faber JJ, Anderson DF, Thornburg KL, Louey S, Giraud GD . Sequential growth of fetal sheep cardiac myocytes in response to simultaneous arterial and venous hypertension. Am J Physiol Regul Integr Comp Physiol 2007;292:R913–9.
Schlüter KD, Wenzel S . Angiotensin II: a hormone involved in and contributing to pro-hypertrophic cardiac networks and target of anti-hypertrophic cross-talks. Pharmacol Ther 2008;119:311–25.
Segar JL, Dalshaug GB, Bedell KA, Smith OM, Scholz TD . Angiotensin II in cardiac pressure-overload hypertrophy in fetal sheep. Am J Physiol Regul Integr Comp Physiol 2001;281:R2037–47.
O’Tierney PF, Anderson DF, Faber JJ, Louey S, Thornburg KL, Giraud GD . Reduced systolic pressure load decreases cell-cycle activity in the fetal sheep heart. Am J Physiol Regul Integr Comp Physiol 2010;299:R573–8.
Jonker SS, Zhang L, Louey S, Giraud GD, Thornburg KL, Faber JJ . Myocyte enlargement, differentiation, and proliferation kinetics in the fetal sheep heart. J Appl Physiol (1985) 2007;102:1130–42.
Barbera A, Giraud GD, Reller MD, Maylie J, Morton MJ, Thornburg KL . Right ventricular systolic pressure load alters myocyte maturation in fetal sheep. Am J Physiol Regul Integr Comp Physiol 2000;279:R1157–64.
Montgomery MO, Jiao Y, Phillips SJ, et al. Alterations in sheep fetal right ventricular tissue with induced hemodynamic pressure overload. Basic Res Cardiol 1998;93:192–200.
Olson AK, Protheroe KN, Scholz TD, Segar JL . The mitogen-activated protein kinases and Akt are developmentally regulated in the chronically anemic fetal sheep heart. J Soc Gynecol Investig 2006;13:157–65.
Braz JC, Bueno OF, Liang Q, et al. Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling. J Clin Invest 2003;111:1475–86.
Liao P, Georgakopoulos D, Kovacs A, et al. The in vivo role of p38 MAP kinases in cardiac remodeling and restrictive cardiomyopathy. Proc Natl Acad Sci USA 2001;98:12283–8.
Kato N, Liang YQ, Ochiai Y, Birukawa N, Serizawa M, Jesmin S . Candesartan-induced gene expression in five organs of stroke-prone spontaneously hypertensive rats. Hypertens Res 2008;31:1963–75.
Brooks WW, Bing OH, Conrad CH, et al. Captopril modifies gene expression in hypertrophied and failing hearts of aged spontaneously hypertensive rats. Hypertension 1997;30:1362–8.
Jin H, Yang R, Awad TA, et al. Effects of early angiotensin-converting enzyme inhibition on cardiac gene expression after acute myocardial infarction. Circulation 2001;103:736–42.
Kang BY, Hu C, Ryu S, et al. Genomics of cardiac remodeling in angiotensin II-treated wild-type and LOX-1-deficient mice. Physiol Genomics 2010;42:42–54.
Montana ES, Littleton JT . Expression profiling of a hypercontraction-induced myopathy in Drosophila suggests a compensatory cytoskeletal remodeling response. J Biol Chem 2006;281:8100–9.
Hu C, Dandapat A, Sun L, et al. Modulation of angiotensin II-mediated hypertension and cardiac remodeling by lectin-like oxidized low-density lipoprotein receptor-1 deletion. Hypertension 2008;52:556–62.
Koitabashi N, Danner T, Zaiman AL, et al. Pivotal role of cardiomyocyte TGF-β signaling in the murine pathological response to sustained pressure overload. J Clin Invest 2011;121:2301–12.
Rosenkranz S . TGF-beta1 and angiotensin networking in cardiac remodeling. Cardiovasc Res 2004;63:423–32.
Smeets PJ, Teunissen BE, Planavila A, et al. Inflammatory pathways are activated during cardiomyocyte hypertrophy and attenuated by peroxisome proliferator-activated receptors PPARalpha and PPARdelta. J Biol Chem 2008;283:29109–18.
Valente AJ, Clark RA, Siddesha JM, Siebenlist U, Chandrasekar B . CIKS (Act1 or TRAF3IP2) mediates angiotensin-II-induced interleukin-18 expression, and Nox2-dependent cardiomyocyte hypertrophy. J Mol Cell Cardiol 2012;53:113–24.
del Vescovo CD, Cotecchia S, Diviani D . A-kinase-anchoring protein-Lbc anchors IκB kinase β to support interleukin-6-mediated cardiomyocyte hypertrophy. Mol Cell Biol 2013;33:14–27.
Papay RS, Shi T, Piascik MT, Naga Prasad SV, Perez DM . α1A-adrenergic receptors regulate cardiac hypertrophy in vivo through interleukin-6 secretion. Mol Pharmacol 2013;83:939–48.
Bernardo BC, Weeks KL, Pretorius L, McMullen JR . Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacol Ther 2010;128:191–227.
Brüel A, Christoffersen TE, Nyengaard JR . Growth hormone increases the proliferation of existing cardiac myocytes and the total number of cardiac myocytes in the rat heart. Cardiovasc Res 2007;76:400–8.
Tseng YT, Yano N, Rojan A, et al. Ontogeny of phosphoinositide 3-kinase signaling in developing heart: effect of acute beta-adrenergic stimulation. Am J Physiol Heart Circ Physiol 2005;289:H1834–42.
MacLellan WR, Schneider MD . Genetic dissection of cardiac growth control pathways. Annu Rev Physiol 2000;62:289–319.
Sundgren NC, Giraud GD, Schultz JM, Lasarev MR, Stork PJ, Thornburg KL . Extracellular signal-regulated kinase and phosphoinositol-3 kinase mediate IGF-1 induced proliferation of fetal sheep cardiomyocytes. Am J Physiol Regul Integr Comp Physiol 2003;285:R1481–9.
Goyal R, Longo LD . Gene expression in sheep carotid arteries: major changes with maturational development. Pediatr Res 2012;72:137–46.
Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ . Basic local alignment search tool. J Mol Biol 1990;215:403–10.
Maglott D, Ostell J, Pruitt KD, Tatusova T . Entrez Gene: gene-centered information at NCBI. Nucleic Acids Res 2005;33(Database issue):D54–8.
Wheeler DL, Barrett T, Benson DA, et al. Database resources of the National Center for Biotechnology Information. Nucleic Acids Res 2007;35(Database issue):D5–12.
Gentleman RC, Carey VJ, Bates DM, et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 2004;5:R80.
Silver JD, Ritchie ME, Smyth GK . Microarray background correction: maximum likelihood estimation for the normal-exponential convolution. Biostatistics 2009;10:352–63.
Smyth GK . Limma: linear models for microarray data. In: Gentleman R, Carey V, Dudoit S, Irizarry R, Huber W, eds. Bioinformatics and Computational Biology Solutions Using R and Bioconductor. New York, NY: Springer, 2005:397–420.
Johnson WE, Li C, Rabinovic A . Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 2007;8:118–27.
Storey JD . A direct approach to false discovery rates. J R Stat Soc 2002;64:479–98.
Author information
Authors and Affiliations
Corresponding author
Supplementary information
Supplementary Table S1
(DOC 2140 kb)
Supplementary Table S2
(DOC 73 kb)
Supplementary Table S3
(DOC 73 kb)
Supplementary Table S4
(DOC 73 kb)
Supplementary Table S5
(DOC 73 kb)
Supplementary Table S6
(DOC 231 kb)
Rights and permissions
About this article
Cite this article
Norris, A., Bahr, T., Scholz, T. et al. Angiotensin II–induced cardiovascular load regulates cardiac remodeling and related gene expression in late-gestation fetal sheep. Pediatr Res 75, 689–696 (2014). https://doi.org/10.1038/pr.2014.37
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/pr.2014.37
This article is cited by
-
Identified plasma proteins related to vascular structure are associated with coarctation of the aorta in children
Italian Journal of Pediatrics (2020)
