Abstract
Excitation–contraction coupling in normal cardiac function is performed with well balanced and coordinated functioning but with complex dynamic interactions between functionally connected membrane ionic currents. However, their genomic investigations provide essential information on the regulation of diseases by their transcripts. Therefore, we examined the gene expression levels of the most important voltage-gated ionic channels such as Na+-channels (SCN5A), Ca2+-channels (CACNA1C and CACNA1H), and K+-channels, including transient outward (KCND2, KCNA2, KCNA5, KCNA8), inward rectifier (KCNJ2, KCNJ12, KCNJ4), and delayed rectifier (KCNB1) in left ventricular tissues from either ischemic or dilated cardiomyopathy (ICM or DCM). We also examined the mRNA levels of ATP-dependent K+-channels (KCNJ11, ABCC9) and ERG-family channels (KCNH2). We further determined the mRNA levels of ryanodine receptors (RyR2; ARVC2), phospholamban (PLB or PLN), SR Ca2+-pump (SERCA2; ATP2A1), an accessory protein FKBP12 (PPIASE), protein kinase A (PPNAD4), and Ca2+/calmodulin-dependent protein kinase II (CAMK2G). The mRNA levels of SCN5A, CACNA1C, and CACNA1H in both groups decreased markedly in the heart samples with similar significance, while KvLQT1 genes were high with depressed Kv4.2. The KCNJ11 and KCNJ12 in both groups were depressed, while the KCNJ4 level was significantly high. More importantly, the KCNA5 gene was downregulated only in the ICM, while the KCNJ2 was upregulated only in the DCM. Besides, mRNA levels of ARVC2 and PLB were significantly high compared to the controls, whereas others (ATP2A1, PPIASE, PPNAD4, and CAMK2G) were decreased. Importantly, the increases of KCNB1 and KCNJ11 were more prominent in the ICM than DCM, while the decreases in ATP2A1 and FKBP1A were more prominent in DCM compared to ICM. Overall, this study was the first to demonstrate that the different levels of changes in gene profiles via different types of cardiomyopathy are prominent particularly in some K+-channels, which provide further information about our knowledge of how remodeling processes can be differentiated in HF originated from different pathological conditions.
Similar content being viewed by others
References
Thom T, Haase N, Rosamond W, Howard VJ, Rumsfeld J, Manolio T, Zheng ZJ, Flegal K, O’Donnell C, Kittner S, Lloyd-Jones D, Goff DC Jr, Hong Y, Adams R, Friday G, Furie K, Gorelick P, Kissela B, Marler J, Meigs J, Roger V, Sidney S, Sorlie P, Steinberger J, Wasserthiel-Smoller S, Wilson M, Wolf P, American Heart Association Statistics C and Stroke Statistics S (2006) Heart disease and stroke statistics–2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 113:e85–e151. https://doi.org/10.1161/CIRCULATIONAHA.105.171600
Schaper J, Froede R, Hein S, Buck A, Hashizume H, Speiser B, Friedl A, Bleese N (1991) Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy. Circulation 83:504–514. https://doi.org/10.1161/01.cir.83.2.504
Hein S, Scholz D, Fujitani N, Rennollet H, Brand T, Friedl A, Schaper J (1994) Altered expression of titin and contractile proteins in failing human myocardium. J Mol Cell Cardiol 26:1291–1306. https://doi.org/10.1006/jmcc.1994.1148
Tomaselli GF, Marban E (1999) Electrophysiological remodeling in hypertrophy and heart failure. Cardiovasc Res 42:270–283. https://doi.org/10.1016/s0008-6363(99)00017-6
Hegyi B, Bossuyt J, Griffiths LG, Shimkunas R, Coulibaly Z, Jian Z, Grimsrud KN, Sondergaard CS, Ginsburg KS, Chiamvimonvat N, Belardinelli L, Varro A, Papp JG, Pollesello P, Levijoki J, Izu LT, Boyd WD, Banyasz T, Bers DM, Chen-Izu Y (2018) Complex electrophysiological remodeling in postinfarction ischemic heart failure. Proc Natl Acad Sci USA 115:E3036–E3044. https://doi.org/10.1073/pnas.1718211115
Coronel R, Wilders R, Verkerk AO, Wiegerinck RF, Benoist D, Bernus O (2013) Electrophysiological changes in heart failure and their implications for arrhythmogenesis. Biochim Biophys Acta 1832:2432–2441. https://doi.org/10.1016/j.bbadis.2013.04.002
Szuts V, Menesi D, Varga-Orvos Z, Zvara A, Houshmand N, Bitay M, Bogats G, Virag L, Baczko I, Szalontai B, Geramipoor A, Cotella D, Wettwer E, Ravens U, Deak F, Puskas LG, Papp JG, Kiss I, Varro A, Jost N (2013) Altered expression of genes for Kir ion channels in dilated cardiomyopathy. Can J Physiol Pharmacol 91:648–656. https://doi.org/10.1139/cjpp-2012-0413
Wang Y, Hill JA (2010) Electrophysiological remodeling in heart failure. J Mol Cell Cardiol 48:619–632. https://doi.org/10.1016/j.yjmcc.2010.01.009
Rahm AK, Lugenbiel P, Schweizer PA, Katus HA, Thomas D (2018) Role of ion channels in heart failure and channelopathies. Biophys Rev 10:1097–1106. https://doi.org/10.1007/s12551-018-0442-3
Tomaselli GF, Zipes DP (2004) What causes sudden death in heart failure? Circ Res 95:754–763. https://doi.org/10.1161/01.RES.0000145047.14691.db
Molina-Navarro MM, Rosello-Lleti E, Ortega A, Tarazon E, Otero M, Martinez-Dolz L, Lago F, Gonzalez-Juanatey JR, Espana F, Garcia-Pavia P, Montero JA, Portoles M, Rivera M (2013) Differential gene expression of cardiac ion channels in human dilated cardiomyopathy. PLoS ONE 8:e79792. https://doi.org/10.1371/journal.pone.0079792
Niggli E, Ullrich ND, Gutierrez D, Kyrychenko S, Polakova E, Shirokova N (2013) Posttranslational modifications of cardiac ryanodine receptors: Ca(2+) signaling and EC-coupling. Biochim Biophys Acta 1833:866–875. https://doi.org/10.1016/j.bbamcr.2012.08.016
Abriel H, Kass RS (2005) Regulation of the voltage-gated cardiac sodium channel Nav1.5 by interacting proteins. Trends Cardiovasc Med 15:35–40. https://doi.org/10.1016/j.tcm.2005.01.001
Gao G, Xie A, Huang SC, Zhou A, Zhang J, Herman AM, Ghassemzadeh S, Jeong EM, Kasturirangan S, Raicu M, Sobieski MA 2nd, Bhat G, Tatooles A, Benz EJ Jr, Kamp TJ, Dudley SC Jr (2011) Role of RBM25/LUC7L3 in abnormal cardiac sodium channel splicing regulation in human heart failure. Circulation 124:1124–1131. https://doi.org/10.1161/CIRCULATIONAHA.111.044495
Dun W, Baba S, Yagi T, Boyden PA (2004) Dynamic remodeling of K+ and Ca2+ currents in cells that survived in the epicardial border zone of canine healed infarcted heart. Am J Physiol Heart Circ Physiol 287:H1046–H1054. https://doi.org/10.1152/ajpheart.00082.2004
McNair WP, Sinagra G, Taylor MR, Di Lenarda A, Ferguson DA, Salcedo EE, Slavov D, Zhu X, Caldwell JH, Mestroni L, Familial Cardiomyopathy Registry Research G (2011) SCN5A mutations associate with arrhythmic dilated cardiomyopathy and commonly localize to the voltage-sensing mechanism. J Am Coll Cardiol 57:2160–2168. https://doi.org/10.1016/j.jacc.2010.09.084
Remme CA (2013) Cardiac sodium channelopathy associated with SCN5A mutations: electrophysiological, molecular and genetic aspects. J Physiol 591:4099–4116. https://doi.org/10.1113/jphysiol.2013.256461
Maltsev VA, Sabbab HN, Undrovinas AI (2002) Down-regulation of sodium current in chronic heart failure: effect of long-term therapy with carvedilol. Cell Mol Life Sci 59:1561–1568
Kaab S, Nuss HB, Chiamvimonvat N, O’Rourke B, Pak PH, Kass DA, Marban E, Tomaselli GF (1996) Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure. Circ Res 78:262–273
Undrovinas AI, Maltsev VA, Sabbah HN (1999) Repolarization abnormalities in cardiomyocytes of dogs with chronic heart failure: role of sustained inward current. Cell Mol Life Sci 55:494–505. https://doi.org/10.1007/s000180050306
Huang B, El-Sherif T, Gidh-Jain M, Qin D, El-Sherif N (2001) Alterations of sodium channel kinetics and gene expression in the postinfarction remodeled myocardium. J Cardiovasc Electrophysiol 12:218–225
Dong M, Niklewski PJ, Wang HS (2011) Ionic mechanisms of cellular electrical and mechanical abnormalities in Brugada syndrome. Am J Physiol Heart Circ Physiol 300:H279–H287. https://doi.org/10.1152/ajpheart.00079.2010
Hasenfuss G, Meyer M, Schillinger W, Preuss M, Pieske B, Just H (1997) Calcium handling proteins in the failing human heart. Basic Res Cardiol 92(Suppl 1):87–93
Beuckelmann DJ, Nabauer M, Erdmann E (1991) Characteristics of calcium-current in isolated human ventricular myocytes from patients with terminal heart failure. J Mol Cell Cardiol 23:929–937
Betzenhauser MJ, Pitt GS, Antzelevitch C (2015) Calcium channel mutations in cardiac arrhythmia syndromes. Curr Mol Pharmacol 8:133–142
Ouadid H, Albat B, Nargeot J (1995) Calcium currents in diseased human cardiac cells. J Cardiovasc Pharmacol 25:282–291
Mukherjee R, Hewett KW, Walker JD, Basler CG, Spinale FG (1998) Changes in L-type calcium channel abundance and function during the transition to pacing-induced congestive heart failure. Cardiovasc Res 37:432–444. https://doi.org/10.1016/s0008-6363(97)00128-4
Yang Y, Chen X, Margulies K, Jeevanandam V, Pollack P, Bailey BA, Houser SR (2000) L-type Ca2+ channel alpha 1c subunit isoform switching in failing human ventricular myocardium. J Mol Cell Cardiol 32:973–984. https://doi.org/10.1006/jmcc.2000.1138
Chen X, Piacentino V 3rd, Furukawa S, Goldman B, Margulies KB, Houser SR (2002) L-type Ca2+ channel density and regulation are altered in failing human ventricular myocytes and recover after support with mechanical assist devices. Circ Res 91:517–524
He J, Conklin MW, Foell JD, Wolff MR, Haworth RA, Coronado R, Kamp TJ (2001) Reduction in density of transverse tubules and L-type Ca(2+) channels in canine tachycardia-induced heart failure. Cardiovasc Res 49:298–307. https://doi.org/10.1016/s0008-6363(00)00256-x
Pitt GS, Dun W, Boyden PA (2006) Remodeled cardiac calcium channels. J Mol Cell Cardiol 41:373–388. https://doi.org/10.1016/j.yjmcc.2006.06.071
Kleiman RB, Houser SR (1988) Calcium currents in normal and hypertrophied isolated feline ventricular myocytes. Am J Physiol 255:H1434–H1442. https://doi.org/10.1152/ajpheart.1988.255.6.H1434
Houser SL, Hashmi FH, Lehmann TJ, Chawla SK (1988) Cardiac surgery in octogenarians: are the risks too high? Conn Med 52:579–581
Clozel JP, Ertel EA, Ertel SI (1999) Voltage-gated T-type Ca2+ channels and heart failure. Proc Assoc Am Physicians 111:429–437
Lipskaia L, Chemaly ER, Hadri L, Lompre AM, Hajjar RJ (2010) Sarcoplasmic reticulum Ca(2+) ATPase as a therapeutic target for heart failure. Expert Opin Biol Ther 10:29–41. https://doi.org/10.1517/14712590903321462
Kawase Y, Hajjar RJ (2008) The cardiac sarcoplasmic/endoplasmic reticulum calcium ATPase: a potent target for cardiovascular diseases. Nat Clin Pract Cardiovasc Med 5:554–565. https://doi.org/10.1038/ncpcardio1301
Han YS, Arroyo J, Ogut O (2013) Human heart failure is accompanied by altered protein kinase A subunit expression and post-translational state. Arch Biochem Biophys 538:25–33. https://doi.org/10.1016/j.abb.2013.08.002
Swaminathan PD, Purohit A, Hund TJ, Anderson ME (2012) Calmodulin-dependent protein kinase II: linking heart failure and arrhythmias. Circ Res 110:1661–1677. https://doi.org/10.1161/CIRCRESAHA.111.243956
Chu G, Kranias EG (2006) Phospholamban as a therapeutic modality in heart failure. Novartis Found Symp 274:156–171 (discussion 172–5, 272–6)
Nagai R, Zarain-Herzberg A, Brandl CJ, Fujii J, Tada M, MacLennan DH, Alpert NR, Periasamy M (1989) Regulation of myocardial Ca2+-ATPase and phospholamban mRNA expression in response to pressure overload and thyroid hormone. Proc Natl Acad Sci USA 86:2966–2970. https://doi.org/10.1073/pnas.86.8.2966
de la Bastie D, Levitsky D, Rappaport L, Mercadier JJ, Marotte F, Wisnewsky C, Brovkovich V, Schwartz K, Lompre AM (1990) Function of the sarcoplasmic reticulum and expression of its Ca2(+)-ATPase gene in pressure overload-induced cardiac hypertrophy in the rat. Circ Res 66:554–564
Mercadier JJ, Lompre AM, Duc P, Boheler KR, Fraysse JB, Wisnewsky C, Allen PD, Komajda M, Schwartz K (1990) Altered sarcoplasmic reticulum Ca2(+)-ATPase gene expression in the human ventricle during end-stage heart failure. J Clin Invest 85:305–309. https://doi.org/10.1172/JCI114429
MacLennan DH, Kranias EG (2003) Phospholamban: a crucial regulator of cardiac contractility. Nat Rev Mol Cell Biol 4:566–577. https://doi.org/10.1038/nrm1151
Anderson ME (2009) Sticky fingers: CaMKII finds a home on another ion channel. Circ Res 104:712–714. https://doi.org/10.1161/CIRCRESAHA.109.195503
Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, Marks AR (2000) PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 101:365–376
Kohlhaas M, Zhang T, Seidler T, Zibrova D, Dybkova N, Steen A, Wagner S, Chen L, Brown JH, Bers DM, Maier LS (2006) Increased sarcoplasmic reticulum calcium leak but unaltered contractility by acute CaMKII overexpression in isolated rabbit cardiac myocytes. Circ Res 98:235–244. https://doi.org/10.1161/01.RES.0000200739.90811.9f
Yuan HX, Yan K, Hou DY, Zhang ZY, Wang H, Wang X, Zhang J, Xu XR, Liang YH, Zhao WS, Xu L, Zhang L (2017) Whole exome sequencing identifies a KCNJ12 mutation as a cause of familial dilated cardiomyopathy. Medicine (Baltimore) 96:e7727. https://doi.org/10.1097/MD.0000000000007727
Yu Y, Wang J, Kang R, Dong J, Zhang Y, Liu F, Yan Y, Zhu R, Xia L, Peng X, Zhang L, He D, Gaisano HY, Chen Z, He Y (2015) Association of KCNB1 polymorphisms with lipid metabolisms and insulin resistance: a case-control design of population-based cross-sectional study in Chinese Han population. Lipids Health Dis 14:112. https://doi.org/10.1186/s12944-015-0115-1
Sun Y, Quan XQ, Fromme S, Cox RH, Zhang P, Zhang L, Guo D, Guo J, Patel C, Kowey PR, Yan GX (2011) A novel mutation in the KCNH2 gene associated with short QT syndrome. J Mol Cell Cardiol 50:433–441. https://doi.org/10.1016/j.yjmcc.2010.11.017
Proks P, Antcliff JF, Lippiat J, Gloyn AL, Hattersley AT, Ashcroft FM (2004) Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features. Proc Natl Acad Sci USA 101:17539–17544. https://doi.org/10.1073/pnas.0404756101
Acknowledgements
The authors would like to thank all technical support from the hospital for their assistance in collection of human tissues. We also would like to thank all the patients and relatives of organ donors who donated samples for this translational study.
Author information
Authors and Affiliations
Contributions
BT designed and supervised the research and provided the final approval of the version to be published; ESK performed the experiments and analyzed the data; ARA and EO are responsible for heart operation; ARA and KCA put forward very valuable comments and interpretation of the data; YO and ET contributed to the experiments by preparing the human tissues for experimental analysis. All authors discussed the results and commented on the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflicts of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Kepenek, E.S., Ozcinar, E., Tuncay, E. et al. Differential expression of genes participating in cardiomyocyte electrophysiological remodeling via membrane ionic mechanisms and Ca2+-handling in human heart failure. Mol Cell Biochem 463, 33–44 (2020). https://doi.org/10.1007/s11010-019-03626-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11010-019-03626-4