Differential expression of genes participating in cardiomyocyte electrophysiological remodeling via membrane ionic mechanisms and Ca2+-handling in human heart failure
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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.
KeywordsChannelopathies Heart failure Voltage-gated ion channels Ryanodine receptors Sodium–calcium exchanger KATP-channels
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.
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.
Compliance with ethical standards
Conflict of interest
The authors declare no conflicts of interest.
- 1.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 Google Scholar
- 5.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 CrossRefGoogle Scholar
- 7.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 CrossRefGoogle Scholar
- 10.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 CrossRefGoogle Scholar
- 11.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 CrossRefGoogle Scholar
- 14.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 CrossRefGoogle Scholar
- 16.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 CrossRefGoogle Scholar
- 33.Houser SL, Hashmi FH, Lehmann TJ, Chawla SK (1988) Cardiac surgery in octogenarians: are the risks too high? Conn Med 52:579–581Google Scholar
- 39.Chu G, Kranias EG (2006) Phospholamban as a therapeutic modality in heart failure. Novartis Found Symp 274:156–171 (discussion 172–5, 272–6) Google Scholar
- 40.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 CrossRefGoogle Scholar
- 41.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 66:554–564CrossRefGoogle Scholar
- 42.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 CrossRefGoogle Scholar
- 46.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 CrossRefGoogle Scholar
- 47.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 CrossRefGoogle Scholar
- 48.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 CrossRefGoogle Scholar