Abstract
Congenital heart disease arises from defects during prenatal heart development. This process is coordinated through a complicated web of intercellular communication between the epicardium, the endocardium, and the myocardium. In the postnatal heart, similar crosstalk between cardiomyocytes, endothelial cells, and fibroblasts exists during pathological hemodynamic overload that emerges as a consequence of a congenital heart defect. Ultimately, communication between cells triggers the activation of select intracellular signaling circuits to mediate hypertrophy in cardiac myocytes. Here, I review the inter- and intracellular signaling mechanisms in the heart as they were discovered mainly in genetically modified mice. The hope is that in the future, targeted therapy of specific molecules or cascades will allow correction of defects that lead to the development of congenital heart disease or pathological hypertrophy.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Towbin JA (2010) Left ventricular noncompaction: a new form of heart failure. Heart Fail Clin 6:453–469
Lemmens K, Doggen K, De Keulenaer GW (2007) Role of neuregulin-1/ErbB signaling in cardiovascular physiology and disease: implications for therapy of heart failure. Circulation 116:954–960
Tian Y, Morrisey EE (2012) Importance of myocyte-nonmyocyte interactions in cardiac development and disease. Circ Res 110:1023–1034
Hertig CM, Kubalak SW, Wang Y et al (1999) Synergistic roles of neuregulin-1 and insulin-like growth factor-i in activation of the phosphatidylinositol 3-kinase pathway and cardiac chamber morphogenesis. J Biol Chem 274:37362–37369
Niessen K, Karsan A (2008) Notch signaling in cardiac development. Circ Res 102:1169–1181
Chen H, Zhang W, Sun X et al (2013) Fkbp1a controls ventricular myocardium trabeculation and compaction by regulating endocardial notch1 activity. Development 140:1946–1957
Lavine KJ, Yu K, White AC et al (2005) Endocardial and epicardial derived FGF signals regulate myocardial proliferation and differentiation in vivo. Dev Cell 8:85–95
Giordano FJ, Gerber HP, Williams SP et al (2001) A cardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function. Proc Natl Acad Sci U S A 98:5780–5785
Shalaby F, Rossant J, Yamaguchi TP et al (1995) Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376:62–66
von Gise A, Pu WT (2012) Endocardial and epicardial epithelial to mesenchymal transitions in heart development and disease. Circ Res 110:1628–1645
Ma L, Lu MF, Schwartz RJ et al (2005) Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning. Development 132:5601–5611
Chen H, Shi S, Acosta L, Li W et al (2004) Bmp10 is essential for maintaining cardiac growth during murine cardiogenesis. Development 131:2219–2231
Lavine KJ, Ornitz DM (2009) Shared circuitry: developmental signaling cascades regulate both embryonic and adult coronary vasculature. Circ Res 104:159–169
Lavine KJ, White AC, Park C et al (2006) Fibroblast growth factor signals regulate a wave of hedgehog activation that is essential for coronary vascular development. Genes Dev 20:1651–1666
Duan J, Gherghe C, Liu D et al (2011) Wnt1/betacatenin injury response activates the epicardium and cardiac fibroblasts to promote cardiac repair. EMBO J 31:429–442
Zhou B, Honor LB, He H et al (2011) Adult mouse epicardium modulates myocardial injury by secreting paracrine factors. J Clin Invest 121:1894–1904
Rudat C, Norden J, Taketo MM et al (2013) Epicardial function of canonical Wnt-, Hedgehog-, Fgfr1/2-, and Pdgfra-signalling. Cardiovasc Res 100:411–421
Vega-Hernandez M, Kovacs A, De Langhe S et al (2011) FGF10/FGFR2b signaling is essential for cardiac fibroblast development and growth of the myocardium. Development 138:3331–3340
Tirziu D, Giordano FJ, Simons M (2010) Cell communications in the heart. Circulation 122:928–937
Gu H, Smith FC, Taffet SM, Delmar M (2003) High incidence of cardiac malformations in connexin40-deficient mice. Circ Res 93:201–206
Biesemann N, Mendler L, Wietelmann A et al (2014) Myostatin regulates energy homeostasis in the heart and prevents heart failure. Circ Res 115:296–310
Heineke J (2012) Wag the dog: how endothelial cells regulate cardiomyocyte growth. Arterioscler Thromb Vasc Biol 32:545–547
Heineke J, Auger-Messier M, Xu J et al (2007) Cardiomyocyte GATA4 functions as a stress-responsive regulator of angiogenesis in the murine heart. J Clin Invest 117:3198–3210
Sano M, Minamino T, Toko H et al (2007) p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload. Nature 446:444–448
Moore-Morris T, Guimaraes-Camboa N, Banerjee I et al (2014) Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis. J Clin Invest 124:2921–2934
Kakkar R, Lee RT (2010) Intramyocardial fibroblast myocyte communication. Circ Res 106:47–57
Ieda M, Tsuchihashi T, Ivey KN et al (2009) Cardiac fibroblasts regulate myocardial proliferation through beta1 integrin signaling. Dev Cell 16:233–244
Takeda N, Manabe I, Uchino Y et al (2010) Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload. J Clin Invest 120:254–265
Viereck J, Bang C, Foinquinos A et al (2014) Regulatory RNAs and paracrine networks in the heart. Cardiovasc Res 102:290–301
Bergmann O, Bhardwaj RD, Bernard S et al (2009) Evidence for cardiomyocyte renewal in humans. Science 324:98–102
Maillet M, van Berlo JH, Molkentin JD (2013) Molecular basis of physiological heart growth: fundamental concepts and new players. Nat Rev Mol Cell Biol 14:38–48
Heineke J, Molkentin JD (2006) Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol 7:589–600
Heineke J, Ritter O (2012) Cardiomyocyte calcineurin signaling in subcellular domains: from the sarcolemma to the nucleus and beyond. J Mol Cell Cardiol 52:62–73
Kreusser MM, Backs J (2014) Integrated mechanisms of CaMKII-dependent ventricular remodeling. Front Pharmacol 5:36
Bourajjaj M, Armand AS, da Costa Martins PA et al (2008) NFATc2 is a necessary mediator of calcineurin-dependent cardiac hypertrophy and heart failure. J Biol Chem 283:22295–22303
Wilkins BJ, De Windt LJ, Bueno OF et al (2002) Targeted disruption of NFATc3, but not NFATc4, reveals an intrinsic defect in calcineurin-mediated cardiac hypertrophic growth. Mol Cell Biol 22:7603–7613
Bueno OF, Lips DJ, Kaiser RA et al (2004) Calcineurin Abeta gene targeting predisposes the myocardium to acute ischemia-induced apoptosis and dysfunction. Circ Res 94:91–99
Kehat I, Davis J, Tiburcy M et al (2011) Extracellular signal-regulated kinases 1 and 2 regulate the balance between eccentric and concentric cardiac growth. Circ Res 108:176–183
Hauck L, Harms C, An J et al (2008) Protein kinase CK2 links extracellular growth factor signaling with the control of p27(Kip1) stability in the heart. Nat Med 14:315–324
Eom GH, Cho YK, Ko JH (2011) Casein kinase-2alpha1 induces hypertrophic response by phosphorylation of histone deacetylase 2 S394 and its activation in the heart. Circulation 123:2392–2403
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer-Verlag Wien
About this chapter
Cite this chapter
Heineke, J. (2016). Inter- and Intracellular Signaling Pathways. In: Rickert-Sperling, S., Kelly, R., Driscoll, D. (eds) Congenital Heart Diseases: The Broken Heart. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1883-2_11
Download citation
DOI: https://doi.org/10.1007/978-3-7091-1883-2_11
Publisher Name: Springer, Vienna
Print ISBN: 978-3-7091-1882-5
Online ISBN: 978-3-7091-1883-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)