Gender-specific Characteristics of Hypertrophic Response in Cardiomyocytes Derived from Human Embryonic Stem Cells

Overview

Journal J Cardiovasc Thorac Res

Specialty Cardiology & Vascular Diseases

Date 2021 Jul 30

PMID 34326969

Citations 1

Authors

Shiva Ahmadvand

Ali Osia

Anna Meyfour

Sara Pahlavan

Affiliations

Soon will be listed here.

Abstract

Gender-specific phenotypes of the heart were reported with respect to both physiology and pathology. While most differences were associated with the sex hormones, differential expression of genes received special attention, particularly X-Y chromosomes' genes. Here, we compared cardiogenesis by gene expression analysis of lineage specific markers and X-Y chromosomes' genes, during differentiation of XY and XX human embryonic stem cells (hESC), in a hormone-free setup. Downregulation of pluripotency marker () and upregulation of cardiac mesoderm and progenitor markers () was remained temporally similar in differentiating XY and XX hESCs. Isoproterenol treatment of XY and XX hESC-derived cardiomyocytes (hESCCM) induced hypertrophy in a sex-specific manner, with female cardiomyocytes showing response at higher isoproterenol concentration and a later time point of differentiation. Interestingly, as an X-linked gene, was markedly upregulated in both hypertrophied male and female cardiomyocytes. Collectively, our results indicated a temporally identical cardiogenesis, but more susceptibility of XY hESC-CM to hypertrophic stimulus in a hormone-free condition.

Citing Articles

The impact of chromosomal sex on cardiometabolic health and disease.

Wiese C, Avetisyan R, Reue K Trends Endocrinol Metab. 2023; 34(10):652-665.

PMID: 37598068 PMC: 11090013. DOI: 10.1016/j.tem.2023.07.003.

References

Regitz-Zagrosek V, Oertelt-Prigione S, Seeland U, Hetzer R . Sex and gender differences in myocardial hypertrophy and heart failure. Circ J. 2010; 74(7):1265-73. DOI: 10.1253/circj.cj-10-0196. View

Yu S, Li Y, Zhao H, Wang Q, Chen P . The Histone Demethylase JMJD1C Regulates CAMKK2-AMPK Signaling to Participate in Cardiac Hypertrophy. Front Physiol. 2020; 11:539. PMC: 7314990. DOI: 10.3389/fphys.2020.00539. View

Luo T, Kim J . The Role of Estrogen and Estrogen Receptors on Cardiomyocytes: An Overview. Can J Cardiol. 2016; 32(8):1017-25. PMC: 4853290. DOI: 10.1016/j.cjca.2015.10.021. View

Nadeau J, Burrage L, Restivo J, Pao Y, Churchill G, Hoit B . Pleiotropy, homeostasis, and functional networks based on assays of cardiovascular traits in genetically randomized populations. Genome Res. 2003; 13(9):2082-91. PMC: 403692. DOI: 10.1101/gr.1186603. View

Meyfour A, Pahlavan S, Ansari H, Baharvand H, Hosseini Salekdeh G . Down-Regulation of a Male-Specific H3K4 Demethylase, , Impairs Cardiomyocyte Differentiation. J Proteome Res. 2019; 18(12):4277-4282. DOI: 10.1021/acs.jproteome.9b00395. View

InanlooRahatloo K, Liang G, Vo D, Ebert A, Nguyen I, Nguyen P . Sex-based differences in myocardial gene expression in recently deceased organ donors with no prior cardiovascular disease. PLoS One. 2017; 12(8):e0183874. PMC: 5574577. DOI: 10.1371/journal.pone.0183874. View

Meyfour A, Ansari H, Pahlavan S, Mirshahvaladi S, Rezaei-Tavirani M, Gourabi H . Y Chromosome Missing Protein, TBL1Y, May Play an Important Role in Cardiac Differentiation. J Proteome Res. 2017; 16(12):4391-4402. DOI: 10.1021/acs.jproteome.7b00391. View

Torres C, Laugesen A, Helin K . Utx is required for proper induction of ectoderm and mesoderm during differentiation of embryonic stem cells. PLoS One. 2013; 8(4):e60020. PMC: 3616089. DOI: 10.1371/journal.pone.0060020. View

Parks R, Howlett S . Sex differences in mechanisms of cardiac excitation-contraction coupling. Pflugers Arch. 2013; 465(5):747-63. PMC: 3651827. DOI: 10.1007/s00424-013-1233-0. View

10.

Fonoudi H, Ansari H, Abbasalizadeh S, Rezaei Larijani M, Kiani S, Hashemizadeh S . A Universal and Robust Integrated Platform for the Scalable Production of Human Cardiomyocytes From Pluripotent Stem Cells. Stem Cells Transl Med. 2015; 4(12):1482-94. PMC: 4675501. DOI: 10.5966/sctm.2014-0275. View

11.

Nakamura M, Sadoshima J . Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol. 2018; 15(7):387-407. DOI: 10.1038/s41569-018-0007-y. View

12.

Isensee J, Witt H, Pregla R, Hetzer R, Regitz-Zagrosek V, Ruiz Noppinger P . Sexually dimorphic gene expression in the heart of mice and men. J Mol Med (Berl). 2007; 86(1):61-74. PMC: 2755745. DOI: 10.1007/s00109-007-0240-z. View

13.

Meyer S, van der Meer P, van Tintelen J, van den Berg M . Sex differences in cardiomyopathies. Eur J Heart Fail. 2014; 16(3):238-47. DOI: 10.1002/ejhf.15. View

14.

Zhang Q, Chen H, Wang L, Liu D, Hill J, Liu Z . The histone trimethyllysine demethylase JMJD2A promotes cardiac hypertrophy in response to hypertrophic stimuli in mice. J Clin Invest. 2011; 121(6):2447-56. PMC: 3104772. DOI: 10.1172/JCI46277. View

15.

Dent M, Tappia P, Dhalla N . Gender differences in cardiac dysfunction and remodeling due to volume overload. J Card Fail. 2010; 16(5):439-49. DOI: 10.1016/j.cardfail.2009.12.017. View

16.

Kararigas G, Fliegner D, Forler S, Klein O, Schubert C, Gustafsson J . Comparative proteomic analysis reveals sex and estrogen receptor β effects in the pressure overloaded heart. J Proteome Res. 2014; 13(12):5829-36. DOI: 10.1021/pr500749j. View

17.

Praktiknjo S, Llamas B, Scott-Boyer M, Picard S, Robert F, Langlais D . Novel effects of chromosome Y on cardiac regulation, chromatin remodeling, and neonatal programming in male mice. Endocrinology. 2013; 154(12):4746-56. DOI: 10.1210/en.2013-1699. View

18.

Lee S, Lee J, Lee S . UTX, a histone H3-lysine 27 demethylase, acts as a critical switch to activate the cardiac developmental program. Dev Cell. 2011; 22(1):25-37. PMC: 4111644. DOI: 10.1016/j.devcel.2011.11.009. View

19.

Wang C, Lee J, Cho Y, Xiao Y, Jin Q, Liu C . UTX regulates mesoderm differentiation of embryonic stem cells independent of H3K27 demethylase activity. Proc Natl Acad Sci U S A. 2012; 109(38):15324-9. PMC: 3458330. DOI: 10.1073/pnas.1204166109. View

20.

Arnold A . Conceptual frameworks and mouse models for studying sex differences in physiology and disease: why compensation changes the game. Exp Neurol. 2014; 259:2-9. PMC: 4125548. DOI: 10.1016/j.expneurol.2014.01.021. View