Congenital Heart Diseases and Biotechnology: Connecting by Connexin

Abstract:

Heart development is a precisely harmonized process of cellular proliferation, migration, differentiation, and integrated morphogenetic interactions, and therefore it is extremely vulnerable to developmental defects that cause congenital heart diseases (CHD). One of the major causes of CHD has been shown to be the mutations in key cardiac channel-forming proteins namely, connexins (Cxs). Cxs are tetra-spanning transmembrane proteins that form gap junction channels and hemichannels on cellular membrane. They allow passage of small molecules or ions between adjacent cells or between cells and the extracellular environment. Studies have revealed that the spatiotemporal expression of Cxs mainly, Cx31.9, Cx40, Cx43, and Cx45 is essentially involved in early developmental events, morphogenetic transformations, maturation, and functional significance of heart. Our lab and others have shown that mutations in gap junction proteins could result in impaired trafficking, misfolding, and improper channel function of these proteins. It has also been shown that differential expressions of cardiac Cxs are associated with pathophysiological conditions of heart. Collectively, these conditions are coupled with abrogated or modified functionality of relevant channels in cardiac tissue, which are associated with many pathological situations, including CHD. Since CHD are a major cause of morbidity, therefore recovery of such kind of heart defects associated with Cxs is extremely important but remains highly challenging. In this review, we will summarize the role of Cxs in development, morphogenesis, maturation, normal function, and pathology of heart, and propose possible bioengineering techniques to recover defects in cardiac tissues related to the modified functions of Cxs.

• Periodical: Advanced Materials Research (Volume 995)
• Pages: 85-112
• DOI: https://doi.org/10.4028/www.scientific.net/AMR.995.85
• Online since: July 2014
• Authors: Naznin Sultana, Nobuhiro Nakamura, Shigehisa Hirose, Koichi Kutsuzawa, Toshihiro Akaike, Kakon Nag*
• Keywords: Cardiomyocyte, Congenital Heart Disease, Connexin, Gap Junction Channel, Gene Delivery, Heart Development, Peptidomimetics

References

[1] G. Schwedler, A. Lindinger, P.E. Lange, U. Sax, J. Olchvary, B. Peters, U. Bauer, H.W. Hense, Frequency and spectrum of congenital heart defects among live births in Germany : a study of the Competence Network for Congenital Heart Defects, Clin Res Cardiol 100 (2011) 1111-1117.

DOI: 10.1007/s00392-011-0355-7

[2] R. Knowles, I. Griebsch, C. Dezateux, J. Brown, C. Bull, C. Wren, Newborn screening for congenital heart defects: a systematic review and cost-effectiveness analysis, Health Technol Assess 9 (2005) 1-152, iii-iv.

DOI: 10.3310/hta9440

[3] J.N. Kirkpatrick, B. Kaufman, Why should we care about ethical and policy challenges in congenital heart disease? World J Pediatr Congenit Heart Surg 4 (2013) 7-9.

DOI: 10.1177/2150135112454666

[4] S. Yuan, S. Zaidi, M. Brueckner, Congenital heart disease: emerging themes linking genetics and development, Curr Opin Genet Dev 23 (2013) 352-359.

DOI: 10.1016/j.gde.2013.05.004

[5] A. Salameh, K. Blanke, I. Daehnert, Role of connexins in human congenital heart disease: the chicken and egg problem, Front Pharmacol 4 (2013) 70.

DOI: 10.3389/fphar.2013.00070

[6] S.C. Mitchell, S.B. Korones, H.W. Berendes, Congenital heart disease in 56,109 births. Incidence and natural history, Circulation 43 (1971) 323-332.

DOI: 10.1161/01.cir.43.3.323

[7] S.F. Seides, R.J. Shemin, A.G. Morrow, Congenital cardiac abnormalities in monozygotic twins. Report and review of the literature, Br Heart J 42 (1979) 742-745.

DOI: 10.1136/hrt.42.6.742

[8] K.Y. Lin, L.C. D'Alessandro, E. Goldmuntz, Genetic testing in congenital heart disease: ethical considerations, World J Pediatr Congenit Heart Surg 4 (2013) 53-57.

DOI: 10.1177/2150135112459523

[9] G.M. Blue, E.P. Kirk, G.F. Sholler, R.P. Harvey, D.S. Winlaw, Congenital heart disease: current knowledge about causes and inheritance, Med J Aust 197 (2012) 155-159.

DOI: 10.5694/mja12.10811

[10] A.C. Fahed, B.D. Gelb, J.G. Seidman, C.E. Seidman, Genetics of congenital heart disease: the glass half empty, Circ Res 112 (2013) 707-720.

DOI: 10.1161/circresaha.112.300853

[11] N. Sultana, K. Nag, K. Hoshijima, D.W. Laird, A. Kawakami, S. Hirose, Zebrafish early cardiac connexin, Cx36.7/Ecx, regulates myofibril orientation and heart morphogenesis by establishing Nkx2.5 expression, Proc Natl Acad Sci U S A 105 (2008) 4763-4768.

DOI: 10.1073/pnas.0708451105

[12] P. Barnett, M. van den Boogaard, V. Christoffels, Localized and temporal gene regulation in heart development, Curr Top Dev Biol 100 (2012) 171-201.

DOI: 10.1016/b978-0-12-387786-4.00004-x

[13] D.J. McCulley, B.L. Black, Transcription factor pathways and congenital heart disease, Curr Top Dev Biol 100 (2012) 253-277.

[14] N.V. Munshi, Gene regulatory networks in cardiac conduction system development, Circ Res 110 (2012) 1525-1537.

DOI: 10.1161/circresaha.111.260026

[15] D. Staudt, D. Stainier, Uncovering the molecular and cellular mechanisms of heart development using the zebrafish, Annu Rev Genet 46 (2012) 397-418.

DOI: 10.1146/annurev-genet-110711-155646

[16] S. John, D. Cesario, J.N. Weiss, Gap junctional hemichannels in the heart, Acta Physiol Scand 179 (2003) 23-31.

DOI: 10.1046/j.1365-201x.2003.01197.x

[17] W.H. Evans, E. De Vuyst, L. Leybaert, The gap junction cellular internet: connexin hemichannels enter the signalling limelight, Biochem. J 397 (2006) 1-14.

DOI: 10.1042/bj20060175

[18] D.W. Laird, Life cycle of connexins in health and disease, Biochem J 394 (2006) 527-543.

[19] M.S. Nielsen, L. Nygaard Axelsen, P.L. Sorgen, V. Verma, M. Delmar, N.H. Holstein-Rathlou, Gap junctions, Compr. Physiol. 2 (2012) 1981-2035.

DOI: 10.1002/cphy.c110051

[20] J.W. Smyth, R.M. Shaw, The gap junction life cycle, Heart Rhythm. 9 (2012) 151-153.

DOI: 10.1016/j.hrthm.2011.07.028

[21] J. Simek, J. Churko, Q. Shao, D.W. Laird, Cx43 has distinct mobility within plasma-membrane domains, indicative of progressive formation of gap-junction plaques, J. Cell. Sci. 122 (2009) 554-562.

DOI: 10.1242/jcs.036970

[22] A. Chandrasekhar, A.K. Bera, Hemichannels: permeants and their effect on development, physiology and death, Cell Biochem. Funct 30 (2012) 89-100.

DOI: 10.1002/cbf.2794

[23] F. Abascal, R. Zardoya, Evolutionary analyses of gap junction protein families, Biochim Biophys. Acta 1828 (2013) 4-14.

DOI: 10.1016/j.bbamem.2012.02.007

[24] V. Cruciani, S.O. Mikalsen, The vertebrate connexin family, Cell Mol Life Sci 63 (2006) 1125-1140.

DOI: 10.1007/s00018-005-5571-8

[25] G. Sohl, K. Willecke, Gap junctions and the connexin protein family, Cardiovasc Res 62 (2004) 228-232.

DOI: 10.1016/j.cardiores.2003.11.013

[26] C.A. Dunn, V. Su, A.F. Lau, P.D. Lampe, Activation of Akt, not connexin 43 protein ubiquitination, regulates gap junction stability, J. Biol. Chem. 287 (2012) 2600-2607.

DOI: 10.1074/jbc.m111.276261

[27] P.D. Lampe, A.F. Lau, The effects of connexin phosphorylation on gap junctional communication, Int J Biochem Cell Biol 36 (2004) 1171-1186.

DOI: 10.1016/s1357-2725(03)00264-4

[28] J. Kronengold, E.B. Trexler, F.F. Bukauskas, T.A. Bargiello, V.K. Verselis, Single-channel SCAM identifies pore-lining residues in the first extracellular loop and first transmembrane domains of Cx46 hemichannels, J Gen Physiol 122 (2003) 389-405.

DOI: 10.1085/jgp.200308861

[29] S. Maeda, S. Nakagawa, M. Suga, E. Yamashita, A. Oshima, Y. Fujiyoshi, T. Tsukihara, Structure of the connexin 26 gap junction channel at 3.5 A resolution, Nature 458 (2009) 597-602.

DOI: 10.1038/nature07869

[30] X.W. Zhou, A. Pfahnl, R. Werner, A. Hudder, A. Llanes, A. Luebke, G. Dahl, Identification of a pore lining segment in gap junction hemichannels, Biophys J 72 (1997) 1946-1953.

DOI: 10.1016/s0006-3495(97)78840-4

[31] J.L. Solan, P.D. Lampe, Connexin43 phosphorylation: structural changes and biological effects, Biochem J 419 (2009) 261-272.

DOI: 10.1042/bj20082319

[32] S. Buvinic, G. Almarza, M. Bustamante, M. Casas, J. Lopez, M. Riquelme, J.C. Saez, J.P. Huidobro-Toro, E. Jaimovich, ATP released by electrical stimuli elicits calcium transients and gene expression in skeletal muscle, J Biol Chem 284 (2009) 34490-34505.

DOI: 10.1074/jbc.m109.057315

[33] P.P. Cherian, A.J. Siller-Jackson, S. Gu, X. Wang, L.F. Bonewald, E. Sprague, J.X. Jiang, Mechanical strain opens connexin 43 hemichannels in osteocytes: a novel mechanism for the release of prostaglandin, Mol Biol Cell 16 (2005) 3100-3106.

DOI: 10.1091/mbc.e04-10-0912

[34] M. Ruiz-Meana, A. Rodriguez-Sinovas, A. Cabestrero, K. Boengler, G. Heusch, D. Garcia-Dorado, Mitochondrial connexin43 as a new player in the pathophysiology of myocardial ischaemia-reperfusion injury, Cardiovasc Res 77 (2008) 325-333.

DOI: 10.1093/cvr/cvm062

[35] M. Nemer, Genetic insights into normal and abnormal heart development, Cardiovasc Pathol 17 (2008) 48-54.

[36] N.J. Severs, The cardiac muscle cell, Bioessays 22 (2000) 188-199.

[37] S. Verheule, S. Kaese, Connexin diversity in the heart: insights from transgenic mouse models, Front Pharmacol 4 (2013) 81.

DOI: 10.3389/fphar.2013.00081

[38] S.C. Chen, L.M. Davis, E.M. Westphale, E.C. Beyer, J.E. Saffitz, Expression of multiple gap junction proteins in human fetal and infant hearts, Pediatr Res 36 (1994) 561-566.

DOI: 10.1203/00006450-199411000-00002

[39] N.C. Chi, M. Bussen, K. Brand-Arzamendi, C. Ding, J.E. Olgin, R.M. Shaw, G.R. Martin, D.Y. Stainier, Cardiac conduction is required to preserve cardiac chamber morphology, Proc Natl Acad Sci U S A 107 (2010) 14662-14667.

DOI: 10.1073/pnas.0909432107

[40] S.R. Coppen, R.A. Kaba, D. Halliday, E. Dupont, J.N. Skepper, S. Elneil, N.J. Severs, Comparison of connexin expression patterns in the developing mouse heart and human foetal heart, Mol Cell Biochem 242 (2003) 121-127.

DOI: 10.1007/978-1-4757-4712-6_16

[41] S.B. Danik, F. Liu, J. Zhang, H.J. Suk, G.E. Morley, G.I. Fishman, D.E. Gutstein, Modulation of cardiac gap junction expression and arrhythmic susceptibility, Circ Res 95 (2004) 1035-1041.

DOI: 10.1161/01.res.0000148664.33695.2a

[42] B. Delorme, E. Dahl, T. Jarry-Guichard, J.P. Briand, K. Willecke, D. Gros, M. Theveniau-Ruissy, Expression pattern of connexin gene products at the early developmental stages of the mouse cardiovascular system, Circ Res 81 (1997) 423-437.

DOI: 10.1161/01.res.81.3.423

[43] L.M. Davis, M.E. Rodefeld, K. Green, E.C. Beyer, J.E. Saffitz, Gap junction protein phenotypes of the human heart and conduction system, J Cardiovasc Electrophysiol 6 (1995) 813-822.

DOI: 10.1111/j.1540-8167.1995.tb00357.x

[44] C. Picoli, V. Nouvel, F. Aubry, M. Reboul, A. Duchene, T. Jeanson, J. Thomasson, F. Mouthon, M. Charveriat, Human connexin channel specificity of classical and new gap junction inhibitors, J Biomol Screen 17 (2012) 1339-1347.

DOI: 10.1177/1087057112452594

[45] L. Miquerol, L. Dupays, M. Theveniau-Ruissy, S. Alcolea, T. Jarry-Guichard, P. Abran, D. Gros, Gap junctional connexins in the developing mouse cardiac conduction system, Novartis Found Symp 250 (2003) 80-98; discussion 98-109, 276-109.

DOI: 10.1002/0470868066.ch6

[46] M.A. Beardslee, J.G. Laing, E.C. Beyer, J.E. Saffitz, Rapid turnover of connexin43 in the adult rat heart, Circ Res 83 (1998) 629-635.

DOI: 10.1161/01.res.83.6.629

[47] A. Salameh, A. Wustmann, S. Karl, K. Blanke, D. Apel, D. Rojas-Gomez, H. Franke, F.W. Mohr, J. Janousek, S. Dhein, Cyclic mechanical stretch induces cardiomyocyte orientation and polarization of the gap junction protein connexin43, Circ Res 106 (2010) 1592-1602.

DOI: 10.1161/circresaha.109.214429

[48] A.G. Reaume, P.A. de Sousa, S. Kulkarni, B.L. Langille, D. Zhu, T.C. Davies, S.C. Juneja, G.M. Kidder, J. Rossant, Cardiac malformation in neonatal mice lacking connexin43, Science 267 (1995) 1831-1834.

DOI: 10.1126/science.7892609

[49] J. Ya, E.B. Erdtsieck-Ernste, P.A. de Boer, M.J. van Kempen, H. Jongsma, D. Gros, A.F. Moorman, W.H. Lamers, Heart defects in connexin43-deficient mice, Circ Res 82 (1998) 360-366.

DOI: 10.1161/01.res.82.3.360

[50] R.J. Francis, C.W. Lo, Primordial germ cell deficiency in the connexin 43 knockout mouse arises from apoptosis associated with abnormal p.53 activation, Development 133 (2006) 3451-3460.

DOI: 10.1242/dev.02506

[51] C.W. Lo, M.F. Cohen, G.Y. Huang, B.O. Lazatin, N. Patel, R. Sullivan, C. Pauken, S.M. Park, Cx43 gap junction gene expression and gap junctional communication in mouse neural crest cells, Dev Genet 20 (1997) 119-132.

DOI: 10.1002/(sici)1520-6408(1997)20:2<119::aid-dvg5>3.0.co;2-a

[52] J.L. Ewart, M.F. Cohen, R.A. Meyer, G.Y. Huang, A. Wessels, R.G. Gourdie, A.J. Chin, S.M. Park, B.O. Lazatin, S. Villabon, C.W. Lo, Heart and neural tube defects in transgenic mice overexpressing the Cx43 gap junction gene, Development 124 (1997) 1281-1292.

DOI: 10.1242/dev.124.7.1281

[53] S.A. Thomas, R.B. Schuessler, C.I. Berul, M.A. Beardslee, E.C. Beyer, M.E. Mendelsohn, J.E. Saffitz, Disparate effects of deficient expression of connexin43 on atrial and ventricular conduction: evidence for chamber-specific molecular determinants of conduction, Circulation 97 (1998) 686-691.

DOI: 10.1161/01.cir.97.7.686

[54] S.H. Britz-Cunningham, M.M. Shah, C.W. Zuppan, W.H. Fletcher, Mutations of the Connexin43 gap-junction gene in patients with heart malformations and defects of laterality, N Engl J Med 332 (1995) 1323-1329.

DOI: 10.1056/nejm199505183322002

[55] N. Kalcheva, J. Qu, N. Sandeep, L. Garcia, J. Zhang, Z. Wang, P.D. Lampe, S.O. Suadicani, D.C. Spray, G.I. Fishman, Gap junction remodeling and cardiac arrhythmogenesis in a murine model of oculodentodigital dysplasia, Proc Natl Acad Sci U S A 104 (2007) 20512-20516.

DOI: 10.1073/pnas.0705472105

[56] J.L. Manias, I. Plante, X.Q. Gong, Q. Shao, J. Churko, D. Bai, D.W. Laird, Fate of connexin43 in cardiac tissue harbouring a disease-linked connexin43 mutant, Cardiovasc Res 80 (2008) 385-395.

DOI: 10.1093/cvr/cvn203

[57] J.M. Tuomi, K. Tyml, D.L. Jones, Atrial tachycardia/fibrillation in the connexin 43 G60S mutant (Oculodentodigital dysplasia) mouse, Am J Physiol Heart Circ Physiol 300 (2011) H1402-1411.

DOI: 10.1152/ajpheart.01094.2010

[58] R. Dobrowolski, P. Sasse, J.W. Schrickel, M. Watkins, J.S. Kim, M. Rackauskas, C. Troatz, A. Ghanem, K. Tiemann, J. Degen, F.F. Bukauskas, R. Civitelli, T. Lewalter, B.K. Fleischmann, K. Willecke, The conditional connexin43G138R mouse mutant represents a new model of hereditary oculodentodigital dysplasia in humans, Hum Mol Genet 17 (2008) 539-554.

DOI: 10.1093/hmg/ddm329

[59] Q. Yu, Y. Shen, B. Chatterjee, B.H. Siegfried, L. Leatherbury, J. Rosenthal, J.F. Lucas, A. Wessels, C.F. Spurney, Y.J. Wu, M.L. Kirby, K. Svenson, C.W. Lo, ENU induced mutations causing congenital cardiovascular anomalies, Development 131 (2004) 6211-6223.

DOI: 10.1242/dev.01543

[60] P. Chen, L.J. Xie, G.Y. Huang, X.Q. Zhao, C. Chang, Mutations of connexin43 in fetuses with congenital heart malformations, Chin Med J (Engl) 118 (2005) 971-976.

[61] B. Wang, Q. Wen, X. Xie, S. Liu, M. Liu, Y. Tao, Z. Li, P. Suo, A. Shen, J. Wang, X. Ma, Mutation analysis of Connexon43 gene in Chinese patients with congenital heart defects, Int J Cardiol 145 (2010) 487-489.

DOI: 10.1016/j.ijcard.2009.06.026

[62] G.Y. Huang, L.J. Xie, K.L. Linask, C. Zhang, X.Q. Zhao, Y. Yang, G.M. Zhou, Y.J. Wu, L. Marquez-Rosado, D.B. McElhinney, E. Goldmuntz, C. Liu, P.D. Lampe, B. Chatterjee, C.W. Lo, Evaluating the role of connexin43 in congenital heart disease: Screening for mutations in patients with outflow tract anomalies and the analysis of knock-in mouse models, J Cardiovasc Dis Res 2 (2011) 206-212.

DOI: 10.4103/0975-3583.89804

[63] S. Elenes, A.D. Martinez, M. Delmar, E.C. Beyer, A.P. Moreno, Heterotypic docking of Cx43 and Cx45 connexons blocks fast voltage gating of Cx43, Biophys J 81 (2001) 1406-1418.

DOI: 10.1016/s0006-3495(01)75796-7

[64] P.A. Guerrero, R.B. Schuessler, L.M. Davis, E.C. Beyer, C.M. Johnson, K.A. Yamada, J.E. Saffitz, Slow ventricular conduction in mice heterozygous for a connexin43 null mutation, J Clin Invest 99 (1997) 1991-1998.

DOI: 10.1172/jci119367

[65] G.E. Morley, D. Vaidya, J. Jalife, Characterization of conduction in the ventricles of normal and heterozygous Cx43 knockout mice using optical mapping, J Cardiovasc Electrophysiol 11 (2000) 375-377.

DOI: 10.1111/j.1540-8167.1999.tb00192.x

[66] D.E. Gutstein, G.E. Morley, G.I. Fishman, Conditional gene targeting of connexin43: exploring the consequences of gap junction remodeling in the heart, Cell Commun Adhes 8 (2001) 345-348.

DOI: 10.3109/15419060109080751

[67] D. Eckardt, M. Theis, J. Degen, T. Ott, H.V. van Rijen, S. Kirchhoff, J.S. Kim, J.M. de Bakker, K. Willecke, Functional role of connexin43 gap junction channels in adult mouse heart assessed by inducible gene deletion, J Mol Cell Cardiol 36 (2004) 101-110.

DOI: 10.1016/j.yjmcc.2003.10.006

[68] M. Kumai, K. Nishii, K. Nakamura, N. Takeda, M. Suzuki, Y. Shibata, Loss of connexin45 causes a cushion defect in early cardiogenesis, Development 127 (2000) 3501-3512.

DOI: 10.1242/dev.127.16.3501

[69] L.M. Davis, H.L. Kanter, E.C. Beyer, J.E. Saffitz, Distinct gap junction protein phenotypes in cardiac tissues with disparate conduction properties, J Am Coll Cardiol 24 (1994) 1124-1132.

DOI: 10.1016/0735-1097(94)90879-6

[70] K. Nishii, M. Kumai, K. Egashira, T. Miwa, K. Hashizume, Y. Miyano, Y. Shibata, Mice lacking connexin45 conditionally in cardiac myocytes display embryonic lethality similar to that of germline knockout mice without endocardial cushion defect, Cell Commun Adhes 10 (2003) 365-369.

DOI: 10.1080/714040454

[71] T. Hisamitsu, T.Y. Nakamura, S. Wakabayashi, Na(+)/H(+) exchanger 1 directly binds to calcineurin A and activates downstream NFAT signaling, leading to cardiomyocyte hypertrophy, Mol Cell Biol 32 (2012) 3265-3280.

DOI: 10.1128/mcb.00145-12

[72] C.P. Chang, J.R. Neilson, J.H. Bayle, J.E. Gestwicki, A. Kuo, K. Stankunas, I.A. Graef, G.R. Crabtree, A field of myocardial-endocardial NFAT signaling underlies heart valve morphogenesis, Cell 118 (2004) 649-663.

DOI: 10.1016/j.cell.2004.08.010

[73] M.D. Combs, C.M. Braitsch, A.W. Lange, J.F. James, K.E. Yutzey, NFATC1 promotes epicardium-derived cell invasion into myocardium, Development 138 (2011) 1747-1757.

DOI: 10.1242/dev.060996

[74] B. Zhou, R.Q. Cron, B. Wu, A. Genin, Z. Wang, S. Liu, P. Robson, H.S. Baldwin, Regulation of the murine Nfatc1 gene by NFATc2, J Biol Chem 277 (2002) 10704-10711.

DOI: 10.1074/jbc.m107068200

[75] M. Frank, A. Wirth, R.P. Andrie, M.M. Kreuzberg, R. Dobrowolski, G. Seifert, S. Offermanns, G. Nickenig, K. Willecke, J.W. Schrickel, Connexin45 provides optimal atrioventricular nodal conduction in the adult mouse heart, Circ Res 111 (2012) 1528-1538.

DOI: 10.1161/circresaha.112.270561

[76] M. Bao, E.M. Kanter, R.Y. Huang, S. Maxeiner, M. Frank, Y. Zhang, R.B. Schuessler, T.W. Smith, R.R. Townsend, H.W. Rohrs, V.M. Berthoud, K. Willecke, J.G. Laing, K.A. Yamada, Residual Cx45 and its relationship to Cx43 in murine ventricular myocardium, Channels (Austin) 5 (2011) 489-499.

DOI: 10.4161/chan.5.6.18523

[77] J.W. Schrickel, M.M. Kreuzberg, A. Ghanem, J.S. Kim, M. Linhart, R. Andrie, K. Tiemann, G. Nickenig, T. Lewalter, K. Willecke, Normal impulse propagation in the atrioventricular conduction system of Cx30.2/Cx40 double deficient mice, J Mol Cell Cardiol 46 (2009) 644-652.

DOI: 10.1016/j.yjmcc.2009.02.012

[78] K. Grikscheit, N. Thomas, A.F. Bruce, S. Rothery, J. Chan, N.J. Severs, E. Dupont, Coexpression of connexin 45 with connexin 43 decreases gap junction size, Cell Commun Adhes 15 (2008) 185-193.

DOI: 10.1080/15419060802013943

[79] B. Delorme, E. Dahl, T. Jarry-Guichard, I. Marics, J.P. Briand, K. Willecke, D. Gros, M. Theveniau-Ruissy, Developmental regulation of connexin 40 gene expression in mouse heart correlates with the differentiation of the conduction system, Dev Dyn 204 (1995) 358-371.

DOI: 10.1002/aja.1002040403

[80] A.M. Simon, D.A. Goodenough, D.L. Paul, Mice lacking connexin40 have cardiac conduction abnormalities characteristic of atrioventricular block and bundle branch block, Curr Biol 8 (1998) 295-298.

DOI: 10.1016/s0960-9822(98)70113-7

[81] B. Sankova, J. Benes, Jr., E. Krejci, L. Dupays, M. Theveniau-Ruissy, L. Miquerol, D. Sedmera, The effect of connexin40 deficiency on ventricular conduction system function during development, Cardiovasc Res 95 (2012) 469-479.

DOI: 10.1093/cvr/cvs210

[82] S. Kirchhoff, J.S. Kim, A. Hagendorff, E. Thonnissen, O. Kruger, W.H. Lamers, K. Willecke, Abnormal cardiac conduction and morphogenesis in connexin40 and connexin43 double-deficient mice, Circ Res 87 (2000) 399-405.

DOI: 10.1161/01.res.87.5.399

[83] H. Gu, F.C. Smith, S.M. Taffet, M. Delmar, High incidence of cardiac malformations in connexin40-deficient mice, Circ Res 93 (2003) 201-206.

DOI: 10.1161/01.res.0000084852.65396.70

[84] K.L. Holler, T.J. Hendershot, S.E. Troy, J.W. Vincentz, A.B. Firulli, M.J. Howard, Targeted deletion of Hand2 in cardiac neural crest-derived cells influences cardiac gene expression and outflow tract development, Dev Biol 341 (2010) 291-304.

DOI: 10.1016/j.ydbio.2010.02.001

[85] V. Guida, R. Ferese, M. Rocchetti, M. Bonetti, A. Sarkozy, S. Cecchetti, V. Gelmetti, F. Lepri, M. Copetti, G. Lamorte, M. Cristina Digilio, B. Marino, A. Zaza, J. den Hertog, B. Dallapiccola, A. De Luca, A variant in the carboxyl-terminus of connexin 40 alters GAP junctions and increases risk for tetralogy of Fallot, Eur J Hum Genet 21 (2013) 69-75.

DOI: 10.1038/ejhg.2012.109

[86] O. Traub, R. Eckert, H. Lichtenberg-Frate, C. Elfgang, B. Bastide, K.H. Scheidtmann, D.F. Hulser, K. Willecke, Immunochemical and electrophysiological characterization of murine connexin40 and -43 in mouse tissues and transfected human cells, Eur J Cell Biol 64 (1994) 101-112.

[87] V. Valiunas, R. Weingart, P.R. Brink, Formation of heterotypic gap junction channels by connexins 40 and 43, Circ Res 86 (2000) E42-49.

DOI: 10.1161/01.res.86.2.e42

[88] G.T. Cottrell, J.M. Burt, Heterotypic gap junction channel formation between heteromeric and homomeric Cx40 and Cx43 connexons, Am J Physiol Cell Physiol 281 (2001) C1559-1567.

DOI: 10.1152/ajpcell.2001.281.5.c1559

[89] G.T. Cottrell, Y. Wu, J.M. Burt, Functional characteristics of heteromeric Cx40-Cx43 gap junction channel formation, Cell Commun Adhes 8 (2001) 193-197.

DOI: 10.3109/15419060109080722

[90] X. Lin, J. Gemel, A. Glass, C.W. Zemlin, E.C. Beyer, R.D. Veenstra, Connexin40 and connexin43 determine gating properties of atrial gap junction channels, J Mol Cell Cardiol 48 (2010) 238-245.

DOI: 10.1016/j.yjmcc.2009.05.014

[91] V.L. Linhares, N.A. Almeida, D.C. Menezes, D.A. Elliott, D. Lai, E.C. Beyer, A.C. Campos de Carvalho, M.W. Costa, Transcriptional regulation of the murine Connexin40 promoter by cardiac factors Nkx2-5, GATA4 and Tbx5, Cardiovasc Res 64 (2004) 402-411.

DOI: 10.1016/j.cardiores.2004.09.021

[92] A. Pizard, P.G. Burgon, D.L. Paul, B.G. Bruneau, C.E. Seidman, J.G. Seidman, Connexin 40, a target of transcription factor Tbx5, patterns wrist, digits, and sternum, Mol Cell Biol 25 (2005) 5073-5083.

DOI: 10.1128/mcb.25.12.5073-5083.2005

[93] D.E. Arnolds, F. Liu, J.P. Fahrenbach, G.H. Kim, K.J. Schillinger, S. Smemo, E.M. McNally, M.A. Nobrega, V.V. Patel, I.P. Moskowitz, TBX5 drives Scn5a expression to regulate cardiac conduction system function, J Clin Invest 122 (2012) 2509-2518.

DOI: 10.1172/jci62617

[94] W.M. Hoogaars, A. Tessari, A.F. Moorman, P.A. de Boer, J. Hagoort, A.T. Soufan, M. Campione, V.M. Christoffels, The transcriptional repressor Tbx3 delineates the developing central conduction system of the heart, Cardiovasc Res 62 (2004) 489-499.

DOI: 10.1016/j.cardiores.2004.01.030

[95] W.T. Aanhaanen, B.J. Boukens, A. Sizarov, V. Wakker, C. de Gier-de Vries, A.C. van Ginneken, A.F. Moorman, R. Coronel, V.M. Christoffels, Defective Tbx2-dependent patterning of the atrioventricular canal myocardium causes accessory pathway formation in mice, J Clin Invest 121 (2011) 534-544.

DOI: 10.1172/jci44350

[96] N. Belluardo, T.W. White, M. Srinivas, A. Trovato-Salinaro, H. Ripps, G. Mudo, R. Bruzzone, D.F. Condorelli, Identification and functional expression of HCx31.9, a novel gap junction gene, Cell Commun Adhes 8 (2001) 173-178.

DOI: 10.3109/15419060109080719

[97] M.M. Kreuzberg, G. Sohl, J.S. Kim, V.K. Verselis, K. Willecke, F.F. Bukauskas, Functional properties of mouse connexin30.2 expressed in the conduction system of the heart, Circ Res 96 (2005) 1169-1177.

DOI: 10.1161/01.res.0000169271.33675.05

[98] J. Gemel, X. Lin, R. Collins, R.D. Veenstra, E.C. Beyer, Cx30.2 can form heteromeric gap junction channels with other cardiac connexins, Biochem Biophys Res Commun 369 (2008) 388-394.

DOI: 10.1016/j.bbrc.2008.02.040

[99] M.M. Kreuzberg, M. Liebermann, S. Segschneider, R. Dobrowolski, H. Dobrzynski, R. Kaba, G. Rowlinson, E. Dupont, N.J. Severs, K. Willecke, Human connexin31.9, unlike its orthologous protein connexin30.2 in the mouse, is not detectable in the human cardiac conduction system, J Mol Cell Cardiol 46 (2009) 553-559.

DOI: 10.1016/j.yjmcc.2008.12.007

[100] S.W. Patterson, H. Piper, E.H. Starling, The regulation of the heart beat, J Physiol 48 (1914) 465-513.

DOI: 10.1113/jphysiol.1914.sp001676

[101] E.H. Starling, M.B. Visscher, The regulation of the energy output of the heart, J Physiol 62 (1927) 243-261.

[102] M.R. Boyett, S. Inada, S. Yoo, J. Li, J. Liu, J. Tellez, I.D. Greener, H. Honjo, R. Billeter, M. Lei, H. Zhang, I.R. Efimov, H. Dobrzynski, Connexins in the sinoatrial and atrioventricular nodes, Adv Cardiol 42 (2006) 175-197.

DOI: 10.1159/000092569

[103] T.A. van Veen, H.V. van Rijen, H.J. Jongsma, Physiology of cardiovascular gap junctions, Adv Cardiol 42 (2006) 18-40.

DOI: 10.1159/000092560

[104] V. Valiunas, D. Manthey, R. Vogel, K. Willecke, R. Weingart, Biophysical properties of mouse connexin30 gap junction channels studied in transfected human HeLa cells, J Physiol 519 Pt 3 (1999) 631-644.

DOI: 10.1111/j.1469-7793.1999.0631n.x

[105] D. Gros, M. Theveniau-Ruissy, M. Bernard, T. Calmels, F. Kober, G. Sohl, K. Willecke, J. Nargeot, H.J. Jongsma, M.E. Mangoni, Connexin 30 is expressed in the mouse sino-atrial node and modulates heart rate, Cardiovasc Res 85 (2010) 45-55.

DOI: 10.1093/cvr/cvp280

[106] K.E. Reed, E.M. Westphale, D.M. Larson, H.Z. Wang, R.D. Veenstra, E.C. Beyer, Molecular cloning and functional expression of human connexin37, an endothelial cell gap junction protein, J Clin Invest 91 (1993) 997-1004.

DOI: 10.1172/jci116321

[107] J.A. Haefliger, R. Polikar, G. Schnyder, M. Burdet, E. Sutter, T. Pexieder, P. Nicod, P. Meda, Connexin37 in normal and pathological development of mouse heart and great arteries, Dev Dyn 218 (2000) 331-344.

DOI: 10.1002/(sici)1097-0177(200006)218:2<331::aid-dvdy7>3.0.co;2-4

[108] S.J. Munger, J.D. Kanady, A.M. Simon, Absence of venous valves in mice lacking Connexin37, Dev Biol 373 (2013) 338-348.

DOI: 10.1016/j.ydbio.2012.10.032

[109] A.M. Simon, A.R. McWhorter, J.A. Dones, C.L. Jackson, H. Chen, Heart and head defects in mice lacking pairs of connexins, Dev Biol 265 (2004) 369-383.

DOI: 10.1016/j.ydbio.2004.04.009

[110] M.G. Hopperstad, M. Srinivas, D.C. Spray, Properties of gap junction channels formed by Cx46 alone and in combination with Cx50, Biophys J 79 (2000) 1954-1966.

DOI: 10.1016/s0006-3495(00)76444-7

[111] E. De Vuyst, E. Decrock, M. De Bock, H. Yamasaki, C.C. Naus, W.H. Evans, L. Leybaert, Connexin hemichannels and gap junction channels are differentially influenced by lipopolysaccharide and basic fibroblast growth factor, Mol Biol Cell 18 (2007) 34-46.

DOI: 10.1091/mbc.e06-03-0182

[112] W.H. Evans, P.E. Martin, Gap junctions: structure and function (Review), Mol Membr Biol 19 (2002) 121-136.

[113] D.E. Gutstein, G.E. Morley, D. Vaidya, F. Liu, F.L. Chen, H. Stuhlmann, G.I. Fishman, Heterogeneous expression of Gap junction channels in the heart leads to conduction defects and ventricular dysfunction, Circulation 104 (2001) 1194-1199.

DOI: 10.1161/hc3601.093990

[114] J.C. Herve, N. Bourmeyster, D. Sarrouilhe, H.S. Duffy, Gap junctional complexes: from partners to functions, Prog Biophys Mol Biol 94 (2007) 29-65.

DOI: 10.1016/j.pbiomolbio.2007.03.010

[115] J.C. Herve, M. Derangeon, B. Bahbouhi, M. Mesnil, D. Sarrouilhe, The connexin turnover, an important modulating factor of the level of cell-to-cell junctional communication: comparison with other integral membrane proteins, J Membr Biol 217 (2007) 21-33.

DOI: 10.1007/s00232-007-9054-8

[116] S. Kaese, S. Verheule, Cardiac electrophysiology in mice: a matter of size, Front Physiol 3 (2012) 345.

[117] B.M. Lewis, A. Pexa, K. Francis, V. Verma, A.M. McNicol, M. Scanlon, A. Deussen, W.H. Evans, D.A. Rees, J. Ham, Adenosine stimulates connexin 43 expression and gap junctional communication in pituitary folliculostellate cells, FASEB J 20 (2006) 2585-2587.

DOI: 10.1096/fj.06-6121fje

[118] M. Oyamada, K. Takebe, Y. Oyamada, Regulation of connexin expression by transcription factors and epigenetic mechanisms, Biochim Biophys Acta 1828 (2013) 118-133.

DOI: 10.1016/j.bbamem.2011.12.031

[119] V.K. Verselis, M. Srinivas, Connexin channel modulators and their mechanisms of action, Neuropharmacology (2013).

DOI: 10.1016/j.neuropharm.2013.03.020

[120] M. Srinivas, M.G. Hopperstad, D.C. Spray, Quinine blocks specific gap junction channel subtypes, Proc Natl Acad Sci U S A 98 (2001) 10942-10947.

DOI: 10.1073/pnas.191206198

[121] H. Musa, E. Fenn, M. Crye, J. Gemel, E.C. Beyer, R.D. Veenstra, Amino terminal glutamate residues confer spermine sensitivity and affect voltage gating and channel conductance of rat connexin40 gap junctions, J Physiol 557 (2004) 863-878.

DOI: 10.1113/jphysiol.2003.059386

[122] G. Dahl, W. Nonner, R. Werner, Attempts to define functional domains of gap junction proteins with synthetic peptides, Biophys J 67 (1994) 1816-1822.

DOI: 10.1016/s0006-3495(94)80663-0

[123] A. Warner, D.K. Clements, S. Parikh, W.H. Evans, R.L. DeHaan, Specific motifs in the external loops of connexin proteins can determine gap junction formation between chick heart myocytes, J Physiol 488 ( Pt 3) (1995) 721-728.

DOI: 10.1113/jphysiol.1995.sp021003

[124] V.M. Berthoud, E.C. Beyer, K.H. Seul, Peptide inhibitors of intercellular communication, Am J Physiol Lung Cell Mol Physiol 279 (2000) L619-622.

DOI: 10.1152/ajplung.2000.279.4.l619

[125] W.H. Evans, G. Bultynck, L. Leybaert, Manipulating connexin communication channels: use of peptidomimetics and the translational outputs, J Membr Biol 245 (2012) 437-449.

DOI: 10.1007/s00232-012-9488-5

[126] C.S. Wright, M.A. van Steensel, M.B. Hodgins, P.E. Martin, Connexin mimetic peptides improve cell migration rates of human epidermal keratinocytes and dermal fibroblasts in vitro, Wound Repair Regen 17 (2009) 240-249.

DOI: 10.1111/j.1524-475x.2009.00471.x

[127] T. Desplantez, V. Verma, L. Leybaert, W.H. Evans, R. Weingart, Gap26, a connexin mimetic peptide, inhibits currents carried by connexin43 hemichannels and gap junction channels, Pharmacol Res 65 (2012) 546-552.

DOI: 10.1016/j.phrs.2012.02.002

[128] N. Wang, M. De Bock, G. Antoons, A.K. Gadicherla, M. Bol, E. Decrock, W.H. Evans, K.R. Sipido, F.F. Bukauskas, L. Leybaert, Connexin mimetic peptides inhibit Cx43 hemichannel opening triggered by voltage and intracellular Ca2+ elevation, Basic Res Cardiol 107 (2012) 304.

DOI: 10.1007/s00395-012-0304-2

[129] E.H. Chowdhury, T. Akaike, High performance DNA nano-carriers of carbonate apatite: multiple factors in regulation of particle synthesis and transfection efficiency, Int J Nanomedicine 2 (2007) 101-106.

DOI: 10.2147/nano.2007.2.1.101

[130] H.L. Jiang, Y.K. Kim, R. Arote, J.W. Nah, M.H. Cho, Y.J. Choi, T. Akaike, C.S. Cho, Chitosan-graft-polyethylenimine as a gene carrier, J Control Release 117 (2007) 273-280.

DOI: 10.1016/j.jconrel.2006.10.025

[131] S.J. Kim, H. Ise, M. Goto, K. Komura, C.S. Cho, T. Akaike, Gene delivery system based on highly specific recognition of surface-vimentin with N-acetylglucosamine immobilized polyethylenimine, Biomaterials 32 (2011) 3471-3480.

DOI: 10.1016/j.biomaterials.2010.12.062

[132] S. Tada, E.H. Chowdhury, C.S. Cho, T. Akaike, pH-sensitive carbonate apatite as an intracellular protein transporter, Biomaterials 31 (2010) 1453-1459.

DOI: 10.1016/j.biomaterials.2009.10.016

[133] F.T. Zohra, Y. Maitani, T. Akaike, mRNA delivery through fibronectin associated liposome-apatite particles: a new approach for enhanced mRNA transfection to mammalian cell, Biol Pharm Bull 35 (2012) 111-115.

DOI: 10.1248/bpb.35.111

[134] D. Xing, A.L. Kjolbye, M.S. Nielsen, J.S. Petersen, K.W. Harlow, N.H. Holstein-Rathlou, J.B. Martins, ZP123 increases gap junctional conductance and prevents reentrant ventricular tachycardia during myocardial ischemia in open chest dogs, J Cardiovasc Electrophysiol 14 (2003) 510-520.

DOI: 10.1046/j.1540-8167.2003.02329.x

[135] T.C. Clarke, D. Thomas, J.S. Petersen, W.H. Evans, P.E. Martin, The antiarrhythmic peptide rotigaptide (ZP123) increases gap junction intercellular communication in cardiac myocytes and HeLa cells expressing connexin 43, Br J Pharmacol 147 (2006) 486-495.

DOI: 10.1038/sj.bjp.0706631

[136] J.M. Guerra, T.H.t. Everett, K.W. Lee, E. Wilson, J.E. Olgin, Effects of the gap junction modifier rotigaptide (ZP123) on atrial conduction and vulnerability to atrial fibrillation, Circulation 114 (2006) 110-118.

DOI: 10.1161/circulationaha.105.606251

[137] J.K. Hennan, R.E. Swillo, G.A. Morgan, E.I. Rossman, J. Kantrowitz, J. Butera, J.S. Petersen, S.J. Gardell, G.P. Vlasuk, GAP-134 ([2S,4R]-1-[2-aminoacetyl]4-benzamidopyrrolidine-2-carboxylic acid) prevents spontaneous ventricular arrhythmias and reduces infarct size during myocardial ischemia/reperfusion injury in open-chest dogs, J. Cardiovasc Pharmacol Ther 14 (2009) 207-214.

DOI: 10.1177/1074248409340779

[138] E.C. Beyer, X. Lin, R.D. Veenstra, Interfering amino terminal peptides and functional implications for heteromeric gap junction formation, Front Pharmacol 4 (2013) 67.

DOI: 10.3389/fphar.2013.00067

[139] D.O. Taylor, L.B. Edwards, P. Aurora, J.D. Christie, F. Dobbels, R. Kirk, A.O. Rahmel, A.Y. Kucheryavaya, M.I. Hertz, Registry of the International Society for Heart and Lung Transplantation: twenty-fifth official adult heart transplant report--2008, J. Heart Lung Transplant 27 (2008) 943-956.

DOI: 10.1016/j.healun.2008.06.017

[140] C.V. Alvarez, M. Garcia-Lavandeira, M.E. Garcia-Rendueles, E. Diaz-Rodriguez, A.R. Garcia-Rendueles, S. Perez-Romero, T.V. Vila, J.S. Rodrigues, P.V. Lear, S.B. Bravo, Defining stem cell types: understanding the therapeutic potential of ESCs, ASCs, and iPS cells, J. Mol. Endocrinol. 49 (2012) R89-111.

DOI: 10.1530/jme-12-0072

[141] D.A. Robinton, G.Q. Daley, The promise of induced pluripotent stem cells in research and therapy, Nature 481 (2012) 295-305.

DOI: 10.1038/nature10761

[142] M. Ieda, Heart regeneration using reprogramming technology, Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 89 (2013) 118-128.

[143] K. Takahashi, S. Yamanaka, Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors, Cell 126 (2006) 663-676.

DOI: 10.1016/j.cell.2006.07.024

[144] K. Takahashi, K. Tanabe, M. Ohnuki, M. Narita, T. Ichisaka, K. Tomoda, S. Yamanaka, Induction of pluripotent stem cells from adult human fibroblasts by defined factors, Cell 131 (2007) 861-872.

DOI: 10.1016/j.cell.2007.11.019

[145] L. Qian, E.C. Berry, J.D. Fu, M. Ieda, D. Srivastava, Reprogramming of mouse fibroblasts into cardiomyocyte-like cells in vitro, Nat. Protoc. 8 (2013) 1204-1215.

DOI: 10.1038/nprot.2013.067

[146] R. Wada, N. Muraoka, K. Inagawa, H. Yamakawa, K. Miyamoto, T. Sadahiro, T. Umei, R. Kaneda, T. Suzuki, K. Kamiya, S. Tohyama, S. Yuasa, K. Kokaji, R. Aeba, R. Yozu, H. Yamagishi, T. Kitamura, K. Fukuda, M. Ieda, Induction of human cardiomyocyte-like cells from fibroblasts by defined factors, Proc Natl Acad Sci U S A (2013).

DOI: 10.1073/pnas.1304053110

[147] A. Minato, H. Ise, M. Goto, T. Akaike, Cardiac differentiation of embryonic stem cells by substrate immobilization of insulin-like growth factor binding protein 4 with elastin-like polypeptides, Biomaterials 33 (2012) 515-523.

DOI: 10.1016/j.biomaterials.2011.09.070

[148] H. Uosaki, H. Fukushima, A. Takeuchi, S. Matsuoka, N. Nakatsuji, S. Yamanaka, J.K. Yamashita, Efficient and scalable purification of cardiomyocytes from human embryonic and induced pluripotent stem cells by VCAM1 surface expression, PLoS One 6 (2011) e23657.

DOI: 10.1371/journal.pone.0023657

[149] N.C. Dubois, A.M. Craft, P. Sharma, D.A. Elliott, E.G. Stanley, A.G. Elefanty, A. Gramolini, G. Keller, SIRPA is a specific cell-surface marker for isolating cardiomyocytes derived from human pluripotent stem cells, Nat. Biotechnol. 29 (2011) 1011-1018.

DOI: 10.1038/nbt.2005

[150] Y. Shiba, S. Fernandes, W.Z. Zhu, D. Filice, V. Muskheli, J. Kim, N.J. Palpant, J. Gantz, K.W. Moyes, H. Reinecke, B. Van Biber, T. Dardas, J.L. Mignone, A. Izawa, R. Hanna, M. Viswanathan, J.D. Gold, M.I. Kotlikoff, N. Sarvazyan, M.W. Kay, C.E. Murry, M.A. Laflamme, Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts, Nature 489 (2012) 322-325.

DOI: 10.1038/nature11317

[151] E. Kim, G.I. Fishman, Designer gap junctions that prevent cardiac arrhythmias, Trends. Cardiovasc. Med. 23 (2013) 33-38.

DOI: 10.1016/j.tcm.2012.08.008

[152] E.L. Scheller, L.G. Villa-Diaz, P.H. Krebsbach, Gene therapy: implications for craniofacial regeneration, J. Craniofac. Surg. 23 (2012) 333-337.

DOI: 10.1097/scs.0b013e318241dc11

[153] N. Tribulova, V. Shneyvays, L.K. Mamedova, S. Moshel, T. Zinman, A. Shainberg, M. Manoach, P. Weismann, S. Kostin, Enhanced connexin-43 and alpha-sarcomeric actin expression in cultured heart myocytes exposed to triiodo-L-thyronine, J. Mol. Histol. 35 (2004) 463-470.

DOI: 10.1023/b:hijo.0000045945.16046.b5

[154] N.A. Almeida, A. Cordeiro, D.S. Machado, L.L. Souza, T.M. Ortiga-Carvalho, A.C. Campos-de-Carvalho, F.E. Wondisford, C.C. Pazos-Moura, Connexin40 messenger ribonucleic acid is positively regulated by thyroid hormone (TH) acting in cardiac atria via the TH receptor, Endocrinology 150 (2009) 546-554.

DOI: 10.1210/en.2008-0451

[155] T.M. Yau, C. Kim, G. Li, Y. Zhang, R.D. Weisel, R.K. Li, Maximizing ventricular function with multimodal cell-based gene therapy, Circulation 112 (2005) I123-128.

DOI: 10.1161/circulationaha.104.525147

[156] J. Yang, W. Zhou, W. Zheng, Y. Ma, L. Lin, T. Tang, J. Liu, J. Yu, X. Zhou, J. Hu, Effects of myocardial transplantation of marrow mesenchymal stem cells transfected with vascular endothelial growth factor for the improvement of heart function and angiogenesis after myocardial infarction, Cardiology 107 (2007) 17-29.

DOI: 10.1159/000093609

[157] M. Delmar, F.X. Liang, Connexin43 and the regulation of intercalated disc function, Heart Rhythm 9 (2012) 835-838.

DOI: 10.1016/j.hrthm.2011.10.028

[158] M. Delmar, N. Makita, Cardiac connexins, mutations and arrhythmias, Curr. Opin. Cardiol. 27 (2012) 236-241.

DOI: 10.1097/hco.0b013e328352220e

[159] G.L. Firestone, B.J. Kapadia, Minireview: regulation of gap junction dynamics by nuclear hormone receptors and their ligands, Mol. Endocrinol. 26 (2012) 1798-1807.

DOI: 10.1210/me.2012-1065

[160] K. Inagawa, M. Ieda, Direct reprogramming of mouse fibroblasts into cardiac myocytes, J. Cardiovasc. Transl. Res. 6 (2013) 37-45.

DOI: 10.1007/s12265-012-9412-5