Molecular and Cellular Biology of the Right Heart

  • Bogdan AmuzescuEmail author
  • Horia Maniu


The present chapter attempts a detailed yet comprehensive account of the exceedingly complex molecular events involved in heart development, including description of the main differentiation signaling pathways, transcription factors, enhancers and gene regulatory networks, with a special emphasis on applying this continuously enlarging body of modern scientific knowledge to the field of stem cell differentiation into cardiomyocytes for diagnostic and therapeutic applications. MicroRNAs are also emerging as an important area of discovery aiming to revolutionize current therapies in cardiology, therefore we describe their involvement in cardiogenesis, proliferation/apoptosis, angiogenesis, fibrosis and hypertrophy. After reviewing the architectural organization, ultrastructure details and functional compartments of cardiomyocytes derived from in vitro and in vivo studies, we focus on molecular mechanisms involved in cardiac hypertrophy and fibrosis, particularly on calcium signaling events triggering these excessive adaptive responses. Further, we stress the embryogenetic and molecular differences between the right and left ventricle, as well as their pathophysiology specificities and clinical consequences.


Heart organizers Differentiation signaling pathways Morphogens Transcription factors Promoters Enhancers Gene regulatory networks Micro RNAs Embryonic stem cells Induced pluripotent stem cells Cardiomyocyte ultrastructure Sarcomere Myofibrils T tubules Diads Sarcoplasmic reticulum Mitochondria Extracellular matrix Proliferation Apoptosis Fibrosis Cardiac hypertrophy Heart failure 



BA expresses his gratitude to Prof. Andrei Dumitru Iacobas for directing his early career in scientific research, and to Prof. Kanigula Mubagwa for introduction in the field of cardiac electrophysiology. This study was funded from Competitiveness Operational Programme 2014–2020 project P_37_675 (contract no. 146/2016), Priority Axis 1, Action 1.1.4, co-financed by the European Funds for Regional Development and Romanian Government funds. The content of this publication does not necessarily reflect the official position of the European Union or Romanian Government.


  1. 1.
    Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145–7.CrossRefGoogle Scholar
  2. 2.
    He JQ, Ma Y, Lee Y, Thomson JA, Kamp TJ. Human embryonic stem cells develop into multiple types of cardiac myocytes: action potential characterization. Circ Res. 2003;93(1):32–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Kehat I, Kenyagin-Karsenti D, Snir M, Segev H, Amit M, Gepstein A, et al. Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest. 2001;108(3):407–14.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Xu C, Police S, Rao N, Carpenter MK. Characterization and enrichment of cardiomyocytes derived from human embryonic stem cells. Circ Res. 2002;91(6):501–8.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Mummery C, Ward-van Oostwaard D, Doevendans P, Spijker R, van den Brink S, Hassink R, et al. Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Circulation. 2003;107(21):2733–40.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Passier R, Oostwaard DW, Snapper J, Kloots J, Hassink RJ, Kuijk E, et al. Increased cardiomyocyte differentiation from human embryonic stem cells in serum-free cultures. Stem Cells. 2005;23(6):772–80.CrossRefPubMedGoogle Scholar
  7. 7.
    Laflamme MA, Chen KY, Naumova AV, Muskheli V, Fugate JA, Dupras SK, et al. Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol. 2007;25(9):1015–24.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Burridge PW, Anderson D, Priddle H, Barbadillo Munoz MD, Chamberlain S, Allegrucci C, et al. Improved human embryonic stem cell embryoid body homogeneity and cardiomyocyte differentiation from a novel V-96 plate aggregation system highlights interline variability. Stem Cells. 2007;25(4):929–38.CrossRefPubMedGoogle Scholar
  9. 9.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.CrossRefGoogle Scholar
  10. 10.
    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.CrossRefPubMedGoogle Scholar
  11. 11.
    Yamanaka S, Blau HM. Nuclear reprogramming to a pluripotent state by three approaches. Nature. 2010;465(7299):704–12.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Aasen T, Raya A, Barrero MJ, Garreta E, Consiglio A, Gonzalez F, et al. Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol. 2008;26(11):1276–84.CrossRefPubMedGoogle Scholar
  13. 13.
    Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318(5858):1917–20.CrossRefPubMedGoogle Scholar
  14. 14.
    Chan KK, Zhang J, Chia NY, Chan YS, Sim HS, Tan KS, et al. KLF4 and PBX1 directly regulate NANOG expression in human embryonic stem cells. Stem Cells. 2009;27(9):2114–25.CrossRefPubMedGoogle Scholar
  15. 15.
    Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S. Generation of mouse induced pluripotent stem cells without viral vectors. Science. 2008;322(5903):949–53.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Chang CW, Lai YS, Pawlik KM, Liu K, Sun CW, Li C, et al. Polycistronic lentiviral vector for “hit and run” reprogramming of adult skin fibroblasts to induced pluripotent stem cells. Stem Cells. 2009;27(5):1042–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Kaji K, Norrby K, Paca A, Mileikovsky M, Mohseni P, Woltjen K. Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature. 2009;458(7239):771–5.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Woltjen K, Michael IP, Mohseni P, Desai R, Mileikovsky M, Hämäläinen R, et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature. 2009;458(7239):766–70.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Lin SL, Chang DC, Lin CH, Ying SY, Leu D, Wu DT. Regulation of somatic cell reprogramming through inducible mir-302 expression. Nucleic Acids Res. 2011;39(3):1054–65.CrossRefPubMedGoogle Scholar
  20. 20.
    Huangfu D, Osafune K, Maehr R, Guo W, Eijkelenboom A, Chen S, et al. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol. 2008;26(11):1269–75.CrossRefPubMedGoogle Scholar
  21. 21.
    Li Y, Zhang Q, Yin X, Yang W, Du Y, Hou P, et al. Generation of iPSCs from mouse fibroblasts with a single gene, Oct4, and small molecules. Cell Res. 2011;21(1):196–204.CrossRefPubMedGoogle Scholar
  22. 22.
    Thorrez L, Sampaolesi M. The future of induced pluripotent stem cells for cardiac therapy and drug development. Curr Pharm Des. 2011;17(30):3258–70.CrossRefPubMedGoogle Scholar
  23. 23.
    Burridge PW, Matsa E, Shukla P, Lin ZC, Churko JM, Ebert AD, et al. Chemically defined generation of human cardiomyocytes. Nat Methods. 2014;11(8):855–60.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Talkhabi M, Aghdami N, Baharvand H. Human cardiomyocyte generation from pluripotent stem cells: a state-of-art. Life Sci. 2016;145:98–113.CrossRefPubMedGoogle Scholar
  25. 25.
    Anson B, Nuwaysir E, Swanson B, Wang WB. Industrialized production of human iPSC-derived cardiomyocytes for use in drug discovery and toxicity testing. BioPharm Int. 2011;2011:58–67.Google Scholar
  26. 26.
    Ma J, Guo L, Fiene SJ, Anson BD, Thomson JA, Kamp TJ, et al. High purity human-induced pluripotent stem cell-derived cardiomyocytes: electrophysiological properties of action potentials and ionic currents. Am J Physiol Heart Circ Physiol. 2011;301(5):2.CrossRefGoogle Scholar
  27. 27.
    Tohyama S, Hattori F, Sano M, Hishiki T, Nagahata Y, Matsuura T, et al. Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes. Cell Stem Cell. 2013;12(1):127–37.CrossRefPubMedGoogle Scholar
  28. 28.
    Hemmi N, Tohyama S, Nakajima K, Kanazawa H, Suzuki T, Hattori F, et al. A massive suspension culture system with metabolic purification for human pluripotent stem cell-derived cardiomyocytes. Stem Cells Transl Med. 2014;3(12):1473–83.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Anderson C, Khan MA, Wong F, Solovieva T, Oliveira NM, Baldock RA, et al. A strategy to discover new organizers identifies a putative heart organizer. Nat Commun. 2016;7:12656.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Kathiriya IS, Nora EP, Bruneau BG. Investigating the transcriptional control of cardiovascular development. Circ Res. 2015;116(4):700–14.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Lints TJ, Parsons LM, Hartley L, Lyons I, Harvey RP. Nkx-2.5: a novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants. Development. 1993;119(2):419–31.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Srivastava D, Cserjesi P, Olson EN. A subclass of bHLH proteins required for cardiac morphogenesis. Science. 1995;270(5244):1995–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Zhong TP, Rosenberg M, Mohideen MA, Weinstein B, Fishman MC. gridlock, an HLH gene required for assembly of the aorta in zebrafish. Science. 2000;287(5459):1820–4.CrossRefPubMedGoogle Scholar
  34. 34.
    Iso T, Kedes L, Hamamori Y. HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol. 2003;194(3):237–55.CrossRefPubMedGoogle Scholar
  35. 35.
    Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, et al. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature. 2003;424(6947):443–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Bruneau BG, Nemer G, Schmitt JP, Charron F, Robitaille L, Caron S, et al. A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease. Cell. 2001;106(6):709–21.CrossRefPubMedGoogle Scholar
  37. 37.
    Koshiba-Takeuchi K, Mori AD, Kaynak BL, Cebra-Thomas J, Sukonnik T, Georges RO, et al. Reptilian heart development and the molecular basis of cardiac chamber evolution. Nature. 2009;461(7260):95–8.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Nadeau M, Georges RO, Laforest B, Yamak A, Lefebvre C, Beauregard J, et al. An endocardial pathway involving Tbx5, Gata4, and Nos3 required for atrial septum formation. Proc Natl Acad Sci U S A. 2010;107(45):19356–61.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, Nagai R, et al. Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation. Nat Genet. 2001;28(3):276–80.CrossRefPubMedGoogle Scholar
  40. 40.
    Nord AS, Blow MJ, Attanasio C, Akiyama JA, Holt A, Hosseini R, et al. Rapid and pervasive changes in genome-wide enhancer usage during mammalian development. Cell. 2013;155(7):1521–31.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Blow MJ, McCulley DJ, Li Z, Zhang T, Akiyama JA, Holt A, et al. ChIP-Seq identification of weakly conserved heart enhancers. Nat Genet. 2010;42(9):806–10.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Wamstad JA, Alexander JM, Truty RM, Shrikumar A, Li F, Eilertson KE, et al. Dynamic and coordinated epigenetic regulation of developmental transitions in the cardiac lineage. Cell. 2012;151(1):206–20.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Neph S, Stergachis AB, Reynolds A, Sandstrom R, Borenstein E, Stamatoyannopoulos JA. Circuitry and dynamics of human transcription factor regulatory networks. Cell. 2012;150(6):1274–86.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Stergachis AB, Neph S, Reynolds A, Humbert R, Miller B, Paige SL, et al. Developmental fate and cellular maturity encoded in human regulatory DNA landscapes. Cell. 2013;154(4):888–903.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Gaulton KJ, Nammo T, Pasquali L, Simon JM, Giresi PG, Fogarty MP, et al. A map of open chromatin in human pancreatic islets. Nat Genet. 2010;42(3):255–9.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Buenrostro JD, Giresi PG, Zaba LC, Chang HY, Greenleaf WJ. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat Methods. 2013;10(12):1213–8.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Knowlton KU, Baracchini E, Ross RS, Harris AN, Henderson SA, Evans SM, et al. Co-regulation of the atrial natriuretic factor and cardiac myosin light chain-2 genes during alpha-adrenergic stimulation of neonatal rat ventricular cells. Identification of cis sequences within an embryonic and a constitutive contractile protein gene which mediate inducible expression. J Biol Chem. 1991;266(12):7759–68.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Seidman CE, Wong DW, Jarcho JA, Bloch KD, Seidman JG. Cis-acting sequences that modulate atrial natriuretic factor gene expression. Proc Natl Acad Sci U S A. 1988;85(11):4104–8.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Sprenkle AB, Murray SF, Glembotski CC. Involvement of multiple cis elements in basal- and alpha-adrenergic agonist-inducible atrial natriuretic factor transcription. Roles for serum response elements and an SP-1-like element. Circ Res. 1995;77(6):1060–9.CrossRefPubMedGoogle Scholar
  50. 50.
    Arnold CD, Gerlach D, Stelzer C, Boryń ŁM, Rath M, Stark A. Genome-wide quantitative enhancer activity maps identified by STARR-seq. Science. 2013;339(6123):1074–7.CrossRefPubMedGoogle Scholar
  51. 51.
    de Wit E, de Laat W. A decade of 3C technologies: insights into nuclear organization. Genes Dev. 2012;26(1):11–24.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Noordermeer D, Duboule D. Chromatin looping and organization at developmentally regulated gene loci. Wiley Interdiscip Rev Dev Biol. 2013;2(5):615–30.CrossRefPubMedGoogle Scholar
  53. 53.
    Dillon N. Factor mediated gene priming in pluripotent stem cells sets the stage for lineage specification. Bioessays. 2012;34(3):194–204.CrossRefPubMedGoogle Scholar
  54. 54.
    Lahn BT. The “occlusis” model of cell fate restriction. Bioessays. 2011;33(1):13–20.CrossRefPubMedGoogle Scholar
  55. 55.
    He A, Kong SW, Ma Q, Pu WT. Co-occupancy by multiple cardiac transcription factors identifies transcriptional enhancers active in heart. Proc Natl Acad Sci U S A. 2011a;108(14):5632–7.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Dupays L, Mohun T. Spatiotemporal regulation of enhancers during cardiogenesis. Cell Mol Life Sci. 2016;2016:6.Google Scholar
  57. 57.
    Wamstad JA, Wang X, Demuren OO, Boyer LA. Distal enhancers: new insights into heart development and disease. Trends Cell Biol. 2014;24(5):294–302.CrossRefPubMedGoogle Scholar
  58. 58.
    Uosaki H, Cahan P, Lee DI, Wang S, Miyamoto M, Fernandez L, et al. Transcriptional landscape of cardiomyocyte maturation. Cell Rep. 2015;13(8):1705–16.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Parikh A, Wu J, Blanton RM, Tzanakakis ES. Signaling pathways and gene regulatory networks in cardiomyocyte differentiation. Tissue Eng Part B Rev. 2015;21(4):377–92.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Chen X, Chakravarty T, Zhang Y, Li X, Zhong JF, Wang C. Single-cell transcriptome and epigenomic reprogramming of cardiomyocyte-derived cardiac progenitor cells. Sci Data. 2016;3(160079):79.Google Scholar
  61. 61.
    Pennisi E. Genomics. ENCODE project writes eulogy for junk DNA. Science. 2012;337(6099):1159–61.CrossRefPubMedGoogle Scholar
  62. 62.
    Seeger FH, Zeiher AM, Dimmeler S. MicroRNAs in stem cell function and regenerative therapy of the heart. Arterioscler Thromb Vasc Biol. 2013;33(8):1739–46.CrossRefPubMedGoogle Scholar
  63. 63.
    Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75(5):843–54.CrossRefPubMedGoogle Scholar
  64. 64.
    Wightman B, Ha I, Ruvkun G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell. 1993;75(5):855–62.CrossRefPubMedGoogle Scholar
  65. 65.
    Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2002;99(24):15524–9.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Condorelli G, Latronico MV, Cavarretta E. microRNAs in cardiovascular diseases: current knowledge and the road ahead. J Am Coll Cardiol. 2014;63(21):2177–87.CrossRefPubMedGoogle Scholar
  67. 67.
    Saxena A, Tabin CJ. miRNA-processing enzyme Dicer is necessary for cardiac outflow tract alignment and chamber septation. Proc Natl Acad Sci U S A. 2010;107(1):87–91.CrossRefPubMedGoogle Scholar
  68. 68.
    Peng Y, Song L, Zhao M, Harmelink C, Debenedittis P, Cui X, et al. Critical roles of miRNA-mediated regulation of TGFbeta signalling during mouse cardiogenesis. Cardiovasc Res. 2014;103(2):258–67.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Chen JF, Murchison EP, Tang R, Callis TE, Tatsuguchi M, Deng Z, et al. Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure. Proc Natl Acad Sci U S A. 2008;105(6):2111–6.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Kwon C, Han Z, Olson EN, Srivastava D. MicroRNA1 influences cardiac differentiation in Drosophila and regulates Notch signaling. Proc Natl Acad Sci U S A. 2005;102(52):18986–91.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Zhao Y, Samal E, Srivastava D. Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature. 2005;436(7048):214–20.CrossRefPubMedGoogle Scholar
  72. 72.
    Elia L, Contu R, Quintavalle M, Varrone F, Chimenti C, Russo MA, et al. Reciprocal regulation of microRNA-1 and insulin-like growth factor-1 signal transduction cascade in cardiac and skeletal muscle in physiological and pathological conditions. Circulation. 2009;120(23):2377–85.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Varrone F, Gargano B, Carullo P, Di Silvestre D, De Palma A, Grasso L, et al. The circulating level of FABP3 is an indirect biomarker of microRNA-1. J Am Coll Cardiol. 2013;61(1):88–95.CrossRefPubMedGoogle Scholar
  74. 74.
    Liu N, Bezprozvannaya S, Williams AH, Qi X, Richardson JA, Bassel-Duby R, et al. microRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart. Genes Dev. 2008;22(23):3242–54.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Wang J, Greene SB, Bonilla-Claudio M, Tao Y, Zhang J, Bai Y, et al. Bmp signaling regulates myocardial differentiation from cardiac progenitors through a MicroRNA-mediated mechanism. Dev Cell. 2010;19(6):903–12.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A. 2005;102(39):13944–9.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Hullinger TG, Montgomery RL, Seto AG, Dickinson BA, Semus HM, Lynch JM, et al. Inhibition of miR-15 protects against cardiac ischemic injury. Circ Res. 2012;110(1):71–81.CrossRefPubMedGoogle Scholar
  78. 78.
    Yamakuchi M, Ferlito M, Lowenstein CJ. miR-34a repression of SIRT1 regulates apoptosis. Proc Natl Acad Sci U S A. 2008;105(36):13421–6.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Boon RA, Iekushi K, Lechner S, Seeger T, Fischer A, Heydt S, et al. MicroRNA-34a regulates cardiac ageing and function. Nature. 2013;495(7439):107–10.CrossRefPubMedGoogle Scholar
  80. 80.
    Aurora AB, Mahmoud AI, Luo X, Johnson BA, van Rooij E, Matsuzaki S, et al. MicroRNA-214 protects the mouse heart from ischemic injury by controlling Ca(2)(+) overload and cell death. J Clin Invest. 2012;122(4):1222–32.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Qian L, Van Laake LW, Huang Y, Liu S, Wendland MF, Srivastava D. miR-24 inhibits apoptosis and represses Bim in mouse cardiomyocytes. J Exp Med. 2011;208(3):549–60.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Frank D, Gantenberg J, Boomgaarden I, Kuhn C, Will R, Jarr KU, et al. MicroRNA-20a inhibits stress-induced cardiomyocyte apoptosis involving its novel target Egln3/PHD3. J Mol Cell Cardiol. 2012;52(3):711–7.CrossRefPubMedGoogle Scholar
  83. 83.
    Liu N, Olson EN. MicroRNA regulatory networks in cardiovascular development. Dev Cell. 2010;18(4):510–25.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Malizia AP, Wang DZ. MicroRNAs in cardiomyocyte development. Wiley Interdiscip Rev Syst Biol Med. 2011;3(2):183–90.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Yan S, Jiao K. Functions of miRNAs during mammalian heart development. Int J Mol Sci. 2016;17(5):E789.CrossRefPubMedGoogle Scholar
  86. 86.
    Fiedler J, Thum T. MicroRNAs in myocardial infarction. Arterioscler Thromb Vasc Biol. 2013;33(2):201–5.CrossRefPubMedGoogle Scholar
  87. 87.
    Salloum FN, Yin C, Kukreja RC. Role of microRNAs in cardiac preconditioning. J Cardiovasc Pharmacol. 2010;56(6):581–8.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Ye Y, Perez-Polo JR, Qian J, Birnbaum Y. The role of microRNA in modulating myocardial ischemia-reperfusion injury. Physiol Genomics. 2011;43(10):534–42.CrossRefPubMedGoogle Scholar
  89. 89.
    Zhu H, Fan GC. Role of microRNAs in the reperfused myocardium towards post-infarct remodelling. Cardiovasc Res. 2012;94(2):284–92.CrossRefPubMedGoogle Scholar
  90. 90.
    Huang F, Zhu X, XQ H, Fang ZF, Tang L, XL L, et al. Mesenchymal stem cells modified with miR-126 release angiogenic factors and activate Notch ligand Delta-like-4, enhancing ischemic angiogenesis and cell survival. Int J Mol Med. 2013;31(2):484–92.CrossRefPubMedGoogle Scholar
  91. 91.
    Bonauer A, Carmona G, Iwasaki M, Mione M, Koyanagi M, Fischer A, et al. MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science. 2009;324(5935):1710–3.CrossRefPubMedGoogle Scholar
  92. 92.
    Wu W, Xiao H, Laguna-Fernandez A, Villarreal G Jr, Wang KC, Geary GG, et al. Flow-dependent regulation of kruppel-like factor 2 is mediated by microRNA-92a. Circulation. 2011;124(5):633–41.CrossRefPubMedGoogle Scholar
  93. 93.
    Bonauer A, Boon RA, Dimmeler S. Vascular microRNAs. Curr Drug Targets. 2010;11(8):943–9.CrossRefPubMedGoogle Scholar
  94. 94.
    Suárez Y, Fernández-Hernando C, Yu J, Gerber SA, Harrison KD, Pober JS, et al. Dicer-dependent endothelial microRNAs are necessary for postnatal angiogenesis. Proc Natl Acad Sci U S A. 2008;105(37):14082–7.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Fiedler J, Jazbutyte V, Kirchmaier BC, Gupta SK, Lorenzen J, Hartmann D, et al. MicroRNA-24 regulates vascularity after myocardial infarction. Circulation. 2011;124(6):720–30.CrossRefPubMedGoogle Scholar
  96. 96.
    Li RC, Tao J, Guo YB, HD W, Liu RF, Bai Y, et al. In vivo suppression of microRNA-24 prevents the transition toward decompensated hypertrophy in aortic-constricted mice. Circ Res. 2013;112(4):601–5.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Yin KJ, Olsen K, Hamblin M, Zhang J, Schwendeman SP, Chen YE. Vascular endothelial cell-specific microRNA-15a inhibits angiogenesis in hindlimb ischemia. J Biol Chem. 2012;287(32):27055–64.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Asgeirsdóttir SA, van Solingen C, Kurniati NF, Zwiers PJ, Heeringa P, van Meurs M, et al. MicroRNA-126 contributes to renal microvascular heterogeneity of VCAM-1 protein expression in acute inflammation. Am J Physiol Renal Physiol. 2012;302(12):14.CrossRefGoogle Scholar
  99. 99.
    Madrigal-Matute J, Rotllan N, Aranda JF, Fernández-Hernando C. MicroRNAs and atherosclerosis. Curr Atheroscler Rep. 2013;15(5):013–0322.CrossRefGoogle Scholar
  100. 100.
    Sun X, Icli B, Wara AK, Belkin N, He S, Kobzik L, et al. MicroRNA-181b regulates NF-kappaB-mediated vascular inflammation. J Clin Invest. 2012;122(6):1973–90.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Huang RS, Hu GQ, Lin B, Lin ZY, Sun CC. MicroRNA-155 silencing enhances inflammatory response and lipid uptake in oxidized low-density lipoprotein-stimulated human THP-1 macrophages. J Investig Med. 2010;58(8):961–7.CrossRefPubMedGoogle Scholar
  102. 102.
    Chen T, Huang Z, Wang L, Wang Y, Wu F, Meng S, et al. MicroRNA-125a-5p partly regulates the inflammatory response, lipid uptake, and ORP9 expression in oxLDL-stimulated monocyte/macrophages. Cardiovasc Res. 2009;83(1):131–9.CrossRefPubMedGoogle Scholar
  103. 103.
    Chen KC, Wang YS, CY H, Chang WC, Liao YC, Dai CY, et al. OxLDL up-regulates microRNA-29b, leading to epigenetic modifications of MMP-2/MMP-9 genes: a novel mechanism for cardiovascular diseases. FASEB J. 2011;25(5):1718–28.CrossRefPubMedGoogle Scholar
  104. 104.
    Lovren F, Pan Y, Quan A, Singh KK, Shukla PC, Gupta N, et al. MicroRNA-145 targeted therapy reduces atherosclerosis. Circulation. 2012;126(11 Suppl 1):S81–90.CrossRefPubMedGoogle Scholar
  105. 105.
    Bauersachs J. miR-21: a central regulator of fibrosis not only in the broken heart. Cardiovasc Res. 2012;96(2):227–9.CrossRefPubMedGoogle Scholar
  106. 106.
    van Rooij E, Sutherland LB, Thatcher JE, DiMaio JM, Naseem RH, Marshall WS, et al. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc Natl Acad Sci U S A. 2008;105(35):13027–32.CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M, et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature. 2008;456(7224):980–4.CrossRefPubMedGoogle Scholar
  108. 108.
    Cheng Y, Liu X, Zhang S, Lin Y, Yang J, Zhang C. MicroRNA-21 protects against the H(2)O(2)-induced injury on cardiac myocytes via its target gene PDCD4. J Mol Cell Cardiol. 2009;47(1):5–14.CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Cheng Y, Zhu P, Yang J, Liu X, Dong S, Wang X, et al. Ischaemic preconditioning-regulated miR-21 protects heart against ischaemia/reperfusion injury via anti-apoptosis through its target PDCD4. Cardiovasc Res. 2010;87(3):431–9.CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Boon RA, Seeger T, Heydt S, Fischer A, Hergenreider E, Horrevoets AJ, et al. MicroRNA-29 in aortic dilation: implications for aneurysm formation. Circ Res. 2011;109(10):1115–9.CrossRefPubMedGoogle Scholar
  111. 111.
    van Rooij E, Sutherland LB, Liu N, Williams AH, McAnally J, Gerard RD, et al. A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. Proc Natl Acad Sci U S A. 2006;103(48):18255–60.CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Pan Z, Sun X, Shan H, Wang N, Wang J, Ren J, et al. MicroRNA-101 inhibited postinfarct cardiac fibrosis and improved left ventricular compliance via the FBJ osteosarcoma oncogene/transforming growth factor-beta1 pathway. Circulation. 2012;126(7):840–50.CrossRefPubMedGoogle Scholar
  113. 113.
    Mercola M, Ruiz-Lozano P, Schneider MD. Cardiac muscle regeneration: lessons from development. Genes Dev. 2011;25(4):299–309.CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Small EM, Olson EN. Pervasive roles of microRNAs in cardiovascular biology. Nature. 2011;469(7330):336–42.CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Ieda M, JD F, Delgado-Olguin P, Vedantham V, Hayashi Y, Bruneau BG, et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell. 2010;142(3):375–86.CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Qian L, Huang Y, Spencer CI, Foley A, Vedantham V, Liu L, et al. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature. 2012;485(7400):593–8.CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Song K, Nam YJ, Luo X, Qi X, Tan W, Huang GN, et al. Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature. 2012;485(7400):599–604.CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Jayawardena TM, Egemnazarov B, Finch EA, Zhang L, Payne JA, Pandya K, et al. MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ Res. 2012;110(11):1465–73.CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Heinrich EM, Dimmeler S. MicroRNAs and stem cells: control of pluripotency, reprogramming, and lineage commitment. Circ Res. 2012;110(7):1014–22.CrossRefPubMedGoogle Scholar
  120. 120.
    Forbes MS, Sperelakis N. Ultrastructure of mammalian cardiac muscle. In: Sperelakis N, editor. Physiology and pathophysiology of the heart. 2nd ed. Boston: Kluwer Academic Publishers; 1989. p. 3–41.CrossRefGoogle Scholar
  121. 121.
    Peters NS, Wit AL. Myocardial architecture and ventricular arrhythmogenesis. Circulation. 1998;97(17):1746–54.CrossRefPubMedGoogle Scholar
  122. 122.
    Gregorio CC, Antin PB. To the heart of myofibril assembly. Trends Cell Biol. 2000;10(9):355–62.CrossRefPubMedGoogle Scholar
  123. 123.
    Huxley HE. Memories of early work on muscle contraction and regulation in the 1950’s and 1960’s. Biochem Biophys Res Commun. 2008;369(1):34–42.CrossRefPubMedGoogle Scholar
  124. 124.
    Eremia D. Is there a continuity of filaments in the sarcomere? J Theor Biol. 1985;112(1):177–81.CrossRefPubMedGoogle Scholar
  125. 125.
    Umazume Y, Fujime S. Electro-optical property of extremely stretched skinned muscle fibers. Biophys J. 1975;15(2 Pt 1):163–80.CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Eremia D. An explanation of shortening heat generation and mechanical performance enhancement during muscle stretch. Sci World J. 2001;1:547–54.CrossRefGoogle Scholar
  127. 127.
    Jin JP. Titin-thin filament interaction and potential role in muscle function. Adv Exp Med Biol. 2000;481:319–33. discussion 34–5CrossRefPubMedGoogle Scholar
  128. 128.
    Burlacu A, Rosca AM, Maniu H, Titorencu I, Dragan E, Jinga V, et al. Promoting effect of 5-azacytidine on the myogenic differentiation of bone marrow stromal cells. Eur J Cell Biol. 2008;87(3):173–84.CrossRefPubMedGoogle Scholar
  129. 129.
    Rosca AM, Matei C, Dragan E, Burlacu A. Cardiomyocyte apoptosis in ischaemia-reperfusion due to the exogenous oxidants at the time of reperfusion. Cell Biol Int. 2012;36(12):1207–15.CrossRefPubMedGoogle Scholar
  130. 130.
    Schaper J, Meiser E, Stammler G. Ultrastructural morphometric analysis of myocardium from dogs, rats, hamsters, mice, and from human hearts. Circ Res. 1985;56(3):377–91.CrossRefPubMedGoogle Scholar
  131. 131.
    Parton RG, Way M, Zorzi N, Stang E. Caveolin-3 associates with developing T-tubules during muscle differentiation. J Cell Biol. 1997;136(1):137–54.CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Simons K, Toomre D. Lipid rafts and signal transduction. Nat Rev Mol Cell Biol. 2000;1(1):31–9.CrossRefPubMedGoogle Scholar
  133. 133.
    Ferrantini C, Crocini C, Coppini R, Vanzi F, Tesi C, Cerbai E, et al. The transverse-axial tubular system of cardiomyocytes. Cell Mol Life Sci. 2013;70(24):4695–710.CrossRefPubMedGoogle Scholar
  134. 134.
    Cannell MB, Cheng H, Lederer WJ. The control of calcium release in heart muscle. Science. 1995;268(5213):1045–9.CrossRefPubMedGoogle Scholar
  135. 135.
    Cheng H, Lederer WJ, Cannell MB. Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle. Science. 1993;262(5134):740–4.CrossRefPubMedGoogle Scholar
  136. 136.
    López-López JR, Shacklock PS, Balke CW, Wier WG. Local calcium transients triggered by single L-type calcium channel currents in cardiac cells. Science. 1995;268(5213):1042–5.CrossRefPubMedGoogle Scholar
  137. 137.
    Zima AV, Picht E, Bers DM, Blatter LA. Partial inhibition of sarcoplasmic reticulum ca release evokes long-lasting ca release events in ventricular myocytes: role of luminal ca in termination of ca release. Biophys J. 2008;94(5):1867–79.CrossRefPubMedPubMedCentralGoogle Scholar
  138. 138.
    Faber GM, Silva J, Livshitz L, Rudy Y. Kinetic properties of the cardiac L-type Ca2+ channel and its role in myocyte electrophysiology: a theoretical investigation. Biophys J. 2007;92(5):1522–43.CrossRefPubMedGoogle Scholar
  139. 139.
    Saucerman JJ, Bers DM. Calmodulin mediates differential sensitivity of CaMKII and calcineurin to local Ca2+ in cardiac myocytes. Biophys J. 2008;95(10):4597–612.CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    Shannon TR, Ginsburg KS, Bers DM. Potentiation of fractional sarcoplasmic reticulum calcium release by total and free intra-sarcoplasmic reticulum calcium concentration. Biophys J. 2000;78(1):334–43.CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    Bers DM. Cardiac excitation-contraction coupling. Nature. 2002;415(6868):198–205.CrossRefGoogle Scholar
  142. 142.
    Giles WR, Noble D. Rigorous phenotyping of cardiac iPSC preparations requires knowledge of their resting potential(s). Biophys J. 2016;110(1):278–80.CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    Gerdes AM, Kasten FH. Morphometric study of endomyocardium and epimyocardium of the left ventricle in adult dogs. Am J Anat. 1980;159(4):389–94.CrossRefPubMedGoogle Scholar
  144. 144.
    Severs NJ, Slade AM, Powell T, Twist VW, Jones GE. Morphometric analysis of the isolated calcium-tolerant cardiac myocyte. Organelle volumes, sarcomere length, plasma membrane surface folds, and intramembrane particle density and distribution. Cell Tissue Res. 1985;240(1):159–68.CrossRefPubMedGoogle Scholar
  145. 145.
    Seidel T, Navankasattusas S, Ahmad A, Diakos NA, WD X, Tristani-Firouzi M, et al. Sheet-like remodeling of the transverse tubular system in human heart failure impairs excitation-contraction coupling and functional recovery by mechanical unloading. Circulation. 2017;135(17):1632–45.CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Bird SD, Doevendans PA, van Rooijen MA, Brutel de la Riviere A, Hassink RJ, Passier R, et al. The human adult cardiomyocyte phenotype. Cardiovasc Res. 2003;58(2):423–34.CrossRefPubMedGoogle Scholar
  147. 147.
    Feric NT, Radisic M. Maturing human pluripotent stem cell-derived cardiomyocytes in human engineered cardiac tissues. Adv Drug Deliv Rev. 2016;96:110–34.CrossRefPubMedGoogle Scholar
  148. 148.
    Piper HM, Jacobson SL, Schwartz P. Determinants of cardiomyocyte development in long-term primary culture. J Mol Cell Cardiol. 1988;20(9):825–35.CrossRefPubMedGoogle Scholar
  149. 149.
    Yau TM, Fung K, Weisel RD, Fujii T, Mickle DA, Li RK. Enhanced myocardial angiogenesis by gene transfer with transplanted cells. Circulation. 2001;104(12 Suppl 1):I218–22.CrossRefPubMedGoogle Scholar
  150. 150.
    Anversa P, Kajstura J. Ventricular myocytes are not terminally differentiated in the adult mammalian heart. Circ Res. 1998;83(1):1–14.CrossRefPubMedGoogle Scholar
  151. 151.
    Anversa P, Olivetti G, Bracchi PG, Loud AV. Postnatal development of the M-band in rat cardiac myofibrils. Circ Res. 1981;48(4):561–8.CrossRefPubMedGoogle Scholar
  152. 152.
    Anversa P, Vitali-Mazza L, Loud AV. Morphometric and autoradiographic study of developing ventricular and atrial myocardium in fetal rats. Lab Investig. 1975;33(6):696–705.PubMedPubMedCentralGoogle Scholar
  153. 153.
    Zak R. Development and proliferative capacity of cardiac muscle cells. Circ Res. 1974;35(suppl II):17–26.Google Scholar
  154. 154.
    Rakusan K. Cardiac growth, maturation, and aging. In: Zak R, editor. Growth of the heart in health and disease. New York: Raven Press; 1984. p. 131–4.Google Scholar
  155. 155.
    Anversa P, Sussman MA, Bolli R. Molecular genetic advances in cardiovascular medicine: focus on the myocyte. Circulation. 2004;109(23):2832–8.CrossRefPubMedPubMedCentralGoogle Scholar
  156. 156.
    Beltrami AP, Urbanek K, Kajstura J, Yan SM, Finato N, Bussani R, et al. Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med. 2001;344(23):1750–7.CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Poveda F, Gil D, Martí E, Andaluz A, Ballester M, Carreras F. Helical structure of the cardiac ventricular anatomy assessed by diffusion tensor magnetic resonance imaging with multiresolution tractography. Rev Esp Cardiol. 2013;66(10):782–90.CrossRefPubMedPubMedCentralGoogle Scholar
  158. 158.
    Capulli AK, MacQueen LA, Sheehy SP, Parker KK. Fibrous scaffolds for building hearts and heart parts. Adv Drug Deliv Rev. 2016;96:83–102.CrossRefPubMedPubMedCentralGoogle Scholar
  159. 159.
    Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabe-Heider F, Walsh S, et al. Evidence for cardiomyocyte renewal in humans. Science. 2009;324(5923):98–102.CrossRefPubMedPubMedCentralGoogle Scholar
  160. 160.
    Gutstein DE, Liu FY, Meyers MB, Choo A, Fishman GI. The organization of adherens junctions and desmosomes at the cardiac intercalated disc is independent of gap junctions. J Cell Sci. 2003;116(Pt 5):875–85.CrossRefPubMedPubMedCentralGoogle Scholar
  161. 161.
    Ting S, Liew SJ, Japson F, Shang F, Chong WK, Reuveny S, et al. Time-resolved video analysis and management system for monitoring cardiomyocyte differentiation processes and toxicology assays. Biotechnol J. 2014;9(5):675–83.CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Kempf H, Andrée B, Zweigerdt R. Large-scale production of human pluripotent stem cell derived cardiomyocytes. Adv Drug Deliv Rev. 2016;96:18–30.CrossRefPubMedPubMedCentralGoogle Scholar
  163. 163.
    Batalov I, Feinberg AW. Differentiation of cardiomyocytes from human pluripotent stem cells using monolayer culture. Biomarkers. 2015;10(Suppl 1):71–6.Google Scholar
  164. 164.
    Kotov G, Iliev A, Landzhov B, Jelev L, Dimitrova IN, Hinova-Palova D. Postnatal changes in the morphology of the myocardium in rat ventricles. Arch Anat Physiol. 2017;2(1):11–7.CrossRefGoogle Scholar
  165. 165.
    Cereghetti GM, Stangherlin A, Martins de Brito O, Chang CR, Blackstone C, Bernardi P, et al. Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proc Natl Acad Sci U S A. 2008;105(41):15803–8.CrossRefPubMedPubMedCentralGoogle Scholar
  166. 166.
    Detmer SA, Chan DC. Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol. 2007;8(11):870–9.CrossRefPubMedGoogle Scholar
  167. 167.
    Kuzmicic J, Del Campo A, López-Crisosto C, Morales PE, Pennanen C, Bravo-Sagua R, et al. Mitochondrial dynamics: a potential new therapeutic target for heart failure. Rev Esp Cardiol. 2011;64(10):916–23.CrossRefPubMedGoogle Scholar
  168. 168.
    Liu SJ. Characterization of functional capacity of adult ventricular myocytes in long-term culture. Int J Cardiol. 2013;168(3):1923–36.CrossRefPubMedGoogle Scholar
  169. 169.
    Schelbert EB, Fonarow GC, Bonow RO, Butler J, Gheorghiade M. Therapeutic targets in heart failure: refocusing on the myocardial interstitium. J Am Coll Cardiol. 2014;63(21):2188–98.CrossRefPubMedGoogle Scholar
  170. 170.
    Rehsia NS, Dhalla NS. Potential of endothelin-1 and vasopressin antagonists for the treatment of congestive heart failure. Heart Fail Rev. 2010;15(1):85–101.CrossRefPubMedGoogle Scholar
  171. 171.
    Pall ML. The NO/ONOO-cycle as the central cause of heart failure. Int J Mol Sci. 2013;14(11):22274–330.CrossRefPubMedPubMedCentralGoogle Scholar
  172. 172.
    Spinale FG, Zile MR. Integrating the myocardial matrix into heart failure recognition and management. Circ Res. 2013;113(6):725–38.CrossRefPubMedPubMedCentralGoogle Scholar
  173. 173.
    Putney JW. Origins of the concept of store-operated calcium entry. Front Biosci. 2011;3:980–4.CrossRefGoogle Scholar
  174. 174.
    Hoth M, Penner R. Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature. 1992;355(6358):353–6.CrossRefPubMedPubMedCentralGoogle Scholar
  175. 175.
    Liao Y, Erxleben C, Abramowitz J, Flockerzi V, Zhu MX, Armstrong DL, et al. Functional interactions among Orai1, TRPCs, and STIM1 suggest a STIM-regulated heteromeric Orai/TRPC model for SOCE/Icrac channels. Proc Natl Acad Sci U S A. 2008;105(8):2895–900.CrossRefPubMedPubMedCentralGoogle Scholar
  176. 176.
    Ong HL, Ambudkar IS. The dynamic complexity of the TRPC1 channelosome. Channels. 2011;5(5):424–31.CrossRefPubMedPubMedCentralGoogle Scholar
  177. 177.
    Cheng KT, Ong HL, Liu X, Ambudkar IS. Contribution and regulation of TRPC channels in store-operated Ca2+ entry. Curr Top Membr. 2013;71:149–79.CrossRefPubMedGoogle Scholar
  178. 178.
    Yuan JP, Kim MS, Zeng W, Shin DM, Huang G, Worley PF, et al. TRPC channels as STIM1-regulated SOCs. Channels. 2009;3(4):221–5.CrossRefPubMedGoogle Scholar
  179. 179.
    Seth M, Zhang ZS, Mao L, Graham V, Burch J, Stiber J, et al. TRPC1 channels are critical for hypertrophic signaling in the heart. Circ Res. 2009;105(10):1023–30.CrossRefPubMedPubMedCentralGoogle Scholar
  180. 180.
    Kiyonaka S, Kato K, Nishida M, Mio K, Numaga T, Sawaguchi Y, et al. Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound. Proc Natl Acad Sci U S A. 2009;106(13):5400–5.CrossRefPubMedPubMedCentralGoogle Scholar
  181. 181.
    Bush EW, Hood DB, Papst PJ, Chapo JA, Minobe W, Bristow MR, et al. Canonical transient receptor potential channels promote cardiomyocyte hypertrophy through activation of calcineurin signaling. J Biol Chem. 2006;281(44):33487–96.CrossRefPubMedGoogle Scholar
  182. 182.
    Nakayama H, Wilkin BJ, Bodi I, Molkentin JD. Calcineurin-dependent cardiomyopathy is activated by TRPC in the adult mouse heart. FASEB J. 2006;20(10):1660–70.CrossRefPubMedPubMedCentralGoogle Scholar
  183. 183.
    Wu X, Eder P, Chang B, Molkentin JD. TRPC channels are necessary mediators of pathologic cardiac hypertrophy. Proc Natl Acad Sci U S A. 2010;107(15):7000–5.CrossRefPubMedPubMedCentralGoogle Scholar
  184. 184.
    Fauconnier J, Lanner JT, Sultan A, Zhang SJ, Katz A, Bruton JD, et al. Insulin potentiates TRPC3-mediated cation currents in normal but not in insulin-resistant mouse cardiomyocytes. Cardiovasc Res. 2007;73(2):376–85.CrossRefPubMedGoogle Scholar
  185. 185.
    Washburn DG, Holt DA, Dodson J, McAtee JJ, Terrell LR, Barton L, et al. The discovery of potent blockers of the canonical transient receptor channels, TRPC3 and TRPC6, based on an anilino-thiazole pharmacophore. Bioorg Med Chem Lett. 2013;23(17):4979–84.CrossRefPubMedGoogle Scholar
  186. 186.
    Kuwahara K, Wang Y, McAnally J, Richardson JA, Bassel-Duby R, Hill JA, et al. TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling. J Clin Invest. 2006;116(12):3114–26.CrossRefPubMedPubMedCentralGoogle Scholar
  187. 187.
    Eder P, Molkentin JD. TRPC channels as effectors of cardiac hypertrophy. Circ Res. 2011;108(2):265–72.CrossRefPubMedGoogle Scholar
  188. 188.
    Kuwahara K, Nakao K. New molecular mechanisms for cardiovascular disease: transcriptional pathways and novel therapeutic targets in heart failure. J Pharmacol Sci. 2011;116(4):337–42.CrossRefPubMedGoogle Scholar
  189. 189.
    Lighthouse JK, Small EM. Transcriptional control of cardiac fibroblast plasticity. J Mol Cell Cardiol. 2016;91:52–60.CrossRefPubMedGoogle Scholar
  190. 190.
    Watanabe H, Murakami M, Ohba T, Takahashi Y, Ito H. TRP channel and cardiovascular disease. Pharmacol Ther. 2008;118(3):337–51.CrossRefPubMedGoogle Scholar
  191. 191.
    Corsten MF, Dennert R, Jochems S, Kuznetsova T, Devaux Y, Hofstra L, et al. Circulating MicroRNA-208b and MicroRNA-499 reflect myocardial damage in cardiovascular disease. Circ Cardiovasc Genet. 2010;3(6):499–506.CrossRefPubMedGoogle Scholar
  192. 192.
    Vogel B, Keller A, Frese KS, Leidinger P, Sedaghat-Hamedani F, Kayvanpour E, et al. Multivariate miRNA signatures as biomarkers for non-ischaemic systolic heart failure. Eur Heart J. 2013;34(36):2812–22.CrossRefPubMedGoogle Scholar
  193. 193.
    Bauters C, Kumarswamy R, Holzmann A, Bretthauer J, Anker SD, Pinet F, et al. Circulating miR-133a and miR-423-5p fail as biomarkers for left ventricular remodeling after myocardial infarction. Int J Cardiol. 2013;168(3):1837–40.CrossRefPubMedGoogle Scholar
  194. 194.
    van Rooij E, Sutherland LB, Qi X, Richardson JA, Hill J, Olson EN. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science. 2007;316(5824):575–9.CrossRefPubMedPubMedCentralGoogle Scholar
  195. 195.
    Carè A, Catalucci D, Felicetti F, Bonci D, Addario A, Gallo P, et al. MicroRNA-133 controls cardiac hypertrophy. Nat Med. 2007;13(5):613–8.CrossRefPubMedGoogle Scholar
  196. 196.
    He B, Xiao J, Ren AJ, Zhang YF, Zhang H, Chen M, et al. Role of miR-1 and miR-133a in myocardial ischemic postconditioning. J Biomed Sci. 2011b;18(22):1423–0127.Google Scholar
  197. 197.
    Myers R, Timofeyev V, Li N, Kim C, Ledford HA, Sirish P, et al. Feedback mechanisms for cardiac-specific microRNAs and cAMP signaling in electrical remodeling. Circ Arrhythm Electrophysiol. 2015;8(4):942–50.CrossRefPubMedPubMedCentralGoogle Scholar
  198. 198.
    Matkovich SJ, Wang W, Tu Y, Eschenbacher WH, Dorn LE, Condorelli G, et al. MicroRNA-133a protects against myocardial fibrosis and modulates electrical repolarization without affecting hypertrophy in pressure-overloaded adult hearts. Circ Res. 2010;106(1):166–75.CrossRefPubMedGoogle Scholar
  199. 199.
    Dong DL, Chen C, Huo R, Wang N, Li Z, YJ T, et al. Reciprocal repression between microRNA-133 and calcineurin regulates cardiac hypertrophy: a novel mechanism for progressive cardiac hypertrophy. Hypertension. 2010;55(4):946–52.CrossRefPubMedGoogle Scholar
  200. 200.
    McGrath J, Somlo S, Makova S, Tian X, Brueckner M. Two populations of node monocilia initiate left-right asymmetry in the mouse. Cell. 2003;114(1):61–73.CrossRefPubMedGoogle Scholar
  201. 201.
    Clapham DE. TRP channels as cellular sensors. Nature. 2003;426(6966):517–24.CrossRefGoogle Scholar
  202. 202.
    Moran MM, Xu H, Clapham DE. TRP ion channels in the nervous system. Curr Opin Neurobiol. 2004;14(3):362–9.CrossRefPubMedGoogle Scholar
  203. 203.
    Pennekamp P, Karcher C, Fischer A, Schweickert A, Skryabin B, Horst J, et al. The ion channel polycystin-2 is required for left-right axis determination in mice. Curr Biol. 2002;12(11):938–43.CrossRefPubMedGoogle Scholar
  204. 204.
    Boulter C, Mulroy S, Webb S, Fleming S, Brindle K, Sandford R. Cardiovascular, skeletal, and renal defects in mice with a targeted disruption of the Pkd1 gene. Proc Natl Acad Sci U S A. 2001;98(21):12174–9.CrossRefPubMedPubMedCentralGoogle Scholar
  205. 205.
    Wu G, D’Agati V, Cai Y, Markowitz G, Park JH, Reynolds DM, et al. Somatic inactivation of Pkd2 results in polycystic kidney disease. Cell. 1998;93(2):177–88.CrossRefPubMedGoogle Scholar
  206. 206.
    Mori AD, Zhu Y, Vahora I, Nieman B, Koshiba-Takeuchi K, Davidson L, et al. Tbx5-dependent rheostatic control of cardiac gene expression and morphogenesis. Dev Biol. 2006;297(2):566–86.CrossRefPubMedGoogle Scholar
  207. 207.
    Ocaña OH, Coskun H, Minguillón C, Murawala P, Tanaka EM, Galcerán J, et al. A right-handed signalling pathway drives heart looping in vertebrates. Nature. 2017;549(7670):86–90.CrossRefPubMedPubMedCentralGoogle Scholar
  208. 208.
    Reddy S, Bernstein D. Molecular mechanisms of right ventricular failure. Circulation. 2015;132(18):1734–42.CrossRefPubMedPubMedCentralGoogle Scholar
  209. 209.
    Morine KJ, Paruchuri V, Qiao X, Aronovitz M, Huggins GS, DeNofrio D, et al. Endoglin selectively modulates transient receptor potential channel expression in left and right heart failure. Cardiovasc Pathol. 2016;25(6):478–82.CrossRefPubMedPubMedCentralGoogle Scholar
  210. 210.
    Rocchetti M, Sala L, Rizzetto R, Staszewsky LI, Alemanni M, Zambelli V, et al. Ranolazine prevents INaL enhancement and blunts myocardial remodelling in a model of pulmonary hypertension. Cardiovasc Res. 2014;104(1):37–48.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biophysics and Physiology, Department of BiologyUniversity of BucharestBucharestRomania
  2. 2.Department of Cellular Therapies and Regenerative Medicine“N. Simionescu” Institute of Cell Biology and PathologyBucharestRomania

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