Advertisement

Basic Research in Cardiology

, 114:40 | Cite as

Connexin 43 dephosphorylation contributes to arrhythmias and cardiomyocyte apoptosis in ischemia/reperfusion hearts

  • Jingyi Xue
  • Xinxin Yan
  • Yutong Yang
  • Min Chen
  • Lulin Wu
  • Zhongshan Gou
  • Zhipeng Sun
  • Shaletanati Talabieke
  • Yuanyuan Zheng
  • Dali LuoEmail author
Original Contribution

Abstract

Connexin 43 (Cx43)-associated gap junctions form electrical and mechanical conduits between adjacent ventricular cardiomyocytes, ensuring coordinate electrical excitation and synchronic contraction for each heartbeat. Cx43 dephosphorylation is a characteristic of ischemia, arrhythmia, and a failing and aging myocardium, but the exact phosphosite(s) triggering myocardial apoptosis and electrical disturbance and its underlying mechanisms are unclear. We previously found that Cx43-serine 282 phosphorylation (pS282) can regulate cardiomyocyte survival and electrical stability. Here, we investigated the hypothesis that S282 dephosphorylation occurs in and contributes to ischemia/reperfusion (I/R)-induced cardiac injury. We found enhanced Cx43-pS262 and Cx43-pS368 but decreased Cx43-pS282 in rat hearts subjected to I/R (30 min/2 h). I/R rats had ventricular arrhythmias and myocardial apoptosis with activation of the p38 mitogen-activated protein kinase (p38)/factor-associated suicide (Fas)/Fas-associating protein with a novel death domain (FADD) pathway. Similarly, S282 dephosphorylation, abnormal Ca2+ transients, cell apoptosis and p38/Fas/FADD activation also occurred in neonatal rat ventricular myocytes exposed to anoxia/reoxygenation (12/6 h). To confirm the causative role of S282 dephosphorylation in cardiac injury, rat hearts were intramyocardially injected with a virus carrying the S282 mutant substituted with alanine (S282A), thus causing arrhythmias and reducing cardiac output and myocardial apoptosis with p38/Fas/FADD pathway activation. Moreover, Cx43-S282A+/− mice displayed arrhythmias and impaired cardiac output with global myocardial apoptosis. Our findings revealed that Cx43 dephosphorylation at S282 triggers arrhythmias and, at least partly, contributes to cardiomyocyte death upon I/R by activating the p38/Fas/FADD pathway, providing a novel molecular mechanism and potential target for protecting against cardiac I/R injury.

Keywords

Connexin 43 Phosphorylation Ischemia/reperfusion Apoptosis Arrhythmia 

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (81370339, 81570206) and the Scientific Research Key Program of Beijing Municipal Commission of Education (KZ201710025023).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

395_2019_748_MOESM1_ESM.tif (3.1 mb)
Supplementary material 1 (TIFF 3174 kb)
395_2019_748_MOESM2_ESM.tif (607 kb)
Supplementary material 2 (TIFF 606 kb)
395_2019_748_MOESM3_ESM.tif (1.1 mb)
Supplementary material 3 (TIFF 1076 kb)
395_2019_748_MOESM4_ESM.tif (963 kb)
Supplementary material 4 (TIFF 963 kb)
395_2019_748_MOESM5_ESM.docx (26 kb)
Supplementary material 5 (DOCX 26 kb)

References

  1. 1.
    Ai X, Pogwizd SM (2005) Connexin 43 downregulation and dephosphorylation in nonischemic heart failure is associated with enhanced colocalized protein phosphatase type 2A. Circ Res 96:54–63.  https://doi.org/10.1161/01.RES.0000152325.07495.5a CrossRefPubMedGoogle Scholar
  2. 2.
    Akhmedov A, Montecucco F, Braunersreuther V, Camici GG, Jakob P, Reiner MF, Glanzmann M, Burger F, Paneni F, Galan K, Pelli G, Vuilleumier N, Belin A, Vallée JP, Mach F, Lüscher TF (2015) Genetic deletion of the adaptor protein p66Shc increases susceptibility to short-term ischaemic myocardial injury via intracellular salvage pathways. Eur Heart J 36:516–526.  https://doi.org/10.1093/eurheartj/ehu400 CrossRefPubMedGoogle Scholar
  3. 3.
    Axelsen LN, Stahlhut M, Mohammed S, Larsen BD, Nielsen MS, Holstein-Rathlou NH, Andersen S, Jensen ON, Hennan JK, Kjølbye AL (2006) Identification of ischemia-regulated phosphorylation sites in connexin43: a possible target for the antiarrhythmic peptide analogue rotigaptide (ZP123). J Mol Cell Cardiol 40:790–798.  https://doi.org/10.1016/j.yjmcc.2006.03.005 CrossRefPubMedGoogle Scholar
  4. 4.
    Bodendiek SB, Raman G (2010) Connexin modulators and their potential targets under the magnifying glass. Curr Med Chem 17:4191–4230CrossRefGoogle Scholar
  5. 5.
    Boengler K, Ruiz-Meana M, Gent S, Ungefug E, Soetkamp D, Miro-Casas E, Cabestrero A, Fernandez-Sanz C, Semenzato M, Di Lisa F, Rohrbach S, Garcia-Dorado D, Heusch G, Schulz R (2012) Mitochondrial connexin 43 impacts on respiratory complex I activity and mitochondrial oxygen consumption. J Cell Mol Med 16:1649–1655.  https://doi.org/10.1111/j.1582-4934.2011.01516.x CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Boengler K, Konietzka I, Buechert A, Heinen Y, Garcia-Dorado D, Heusch G, Schulz R (2007) Loss of ischemic preconditioning’s cardioprotection in aged mouse hearts is associated with reduced gap junctional and mitochondrial levels of connexin 43. Am J Physiol Heart Circ Physiol 292:H1764–H1769CrossRefGoogle Scholar
  7. 7.
    Boengler K, Dodoni G, Rodriguez-Sinovas A, Cabestrero A, Ruiz-Meana M, Gres P, Konietzka I, Lopez-Iglesias C, Garcia-Dorado D, Di-Lisa F, Heusch G, Schulz R (2005) Connexin 43 in cardiomyocyte mitochondria and its increase by ischemic preconditioning. Cardiovasc Res 67:234–244.  https://doi.org/10.1016/j.cardiores.2005.04.014 CrossRefPubMedGoogle Scholar
  8. 8.
    Chouchani ET, Pell VR, Gaude E, Aksentijević D, Sundier SY, Robb EL, Logan A, Nadtochiy SM, Ord ENJ, Smith AC, Eyassu F, Shirley R, Hu CH, Dare AJ, James AM, Rogatti S, Hartley RC, Eaton S, Costa ASH, Brookes PS, Davidson SM, Duchen MR, Kourosh SP, Shattock MJ, Robinson AJ, Work LM, Frezza C, Krieg T, Murphy MP (2014) Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515:431–435.  https://doi.org/10.1038/nature13909 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Chu M, Novak SM, Cover C, Wang AA, Chinyereir Juneman EB, Zarnescu DC, Wong PK, Gregorio CC (2018) Increased cardiac arrhythmogenesis associated with gap junction remodeling with upregulation of RNA-binding protein FXR1. Circulation 137:605–618.  https://doi.org/10.1161/CIRCULATIONAHA.117.028976 CrossRefPubMedGoogle Scholar
  10. 10.
    de Diego C, Pai RK, Chen F, Xie LH, De Leeuw J, Weiss JN, Valderrábano M (2008) Electrophysiological consequences of acute regional ischemia/reperfusion in neonatal rat ventricular myocyte monolayers. Circulation 118:2330–2337.  https://doi.org/10.1161/CIRCULATIONAHA.108.789149 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    De Nicola GF, Martin ED, Chaikuad A, Bassi R, Clark J, Martino L, Verma S, Sicard P, Tata R, Atkinson RA, Knapp S, Conte MR, Marber MS (2013) Mechanism and consequence of the autoactivation of p38alpha mitogen-activated protein kinase promoted by TAB 1. Nat Struct Mol Biol 20:1182–1190.  https://doi.org/10.1038/nsmb.2668 CrossRefGoogle Scholar
  12. 12.
    Decrock E, Vinken M, De Vuyst E, Krysko DV, D’Herde K, Vanhaecke T, Vandenabeele P, Rogiers V, Leybaert L (2009) Connexin-related signaling in cell death: to live or let die? Cell Death Differ 16:524–536.  https://doi.org/10.1038/cdd.2008.196 CrossRefPubMedGoogle Scholar
  13. 13.
    Dunn CA, Lampe PD (2014) Injury-triggered Akt phosphorylation of Cx43: a ZO-1-driven molecular switch that regulates gap junction size. J Cell Biol 127:455–464.  https://doi.org/10.1242/jcs.142497 CrossRefGoogle Scholar
  14. 14.
    Elgenaidi IS, Spiers JP (2019) Regulation of the phosphoprotein phosphatase 2A system and its modulation during oxidative stress: a potential therapeutic target? Pharmacol Ther.  https://doi.org/10.1016/j.pharmthera.2019.02.011 CrossRefPubMedGoogle Scholar
  15. 15.
    Eltzschig HK, Eckle T (2011) Ischemia and reperfusion-from mechanism to translation. Nat Med 17:1391–1401.  https://doi.org/10.1038/nm.2507 CrossRefGoogle Scholar
  16. 16.
    Engel FB, Hsieh PC, Lee RT, Keating MT (2006) FGF1/p38 MAP kinase inhibitor therapy induces cardiomyocyte mitosis, reduces scarring, and rescues function after myocardial infarction. Proc Natl Acad Sci USA 103:15546–15551.  https://doi.org/10.1073/pnas.0607382 CrossRefPubMedGoogle Scholar
  17. 17.
    Fan GC, Ren X, Qian J, Yuan Q, Nicolaou P, Wang Y, Jones WK, Chu G, Kranias EG (2005) Novel cardioprotective role of a small heat-shock protein, Hsp20, against ischemia/reperfusion injury. Circulation 111:1792–1799.  https://doi.org/10.1161/01.CIR.0000160851.41872.C6 CrossRefPubMedGoogle Scholar
  18. 18.
    Garcia-Dorado D, Inserte J, Ruiz-Meana M, Gonzales MA, Solares J, Julia M, Barrabes JA, Soler-Soler J (1997) Gap junction uncoupler heptanol prevents cell-to-cell progression of hypercontracture and limits necrosis during myocardial reperfusion. Circulation 96:3579–3586CrossRefGoogle Scholar
  19. 19.
    Glukhov AV, Fedorov VV, Kalish PW, Ravikumar VK, Lou Q, Janks D, Schuessler RB, Moazami N, Efimov IR (2012) Conduction remodeling in human end-stage non-ischemic left ventricular cardiomyopathy. Circulation 125:1835–1847.  https://doi.org/10.1161/CIRCULATIONAHA.111.047274 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Heinzel FR, Luo Y, Li X, Boengler K, Buechert A, García-Dorado D, Di Lisa F, Schulz R, Heusch G (2005) Impairment of diazoxide-induced formation of reactive oxygen species and loss of cardioprotection in connexin 43 deficient mice. Circ Res 97:583–586.  https://doi.org/10.1161/01.RES.0000181171.65293.65 CrossRefPubMedGoogle Scholar
  21. 21.
    Hood AR, Ai X, Pogwizd SM (2017) Regulation of cardiac gap junctions by protein phosphatases. J Mol Cell Cardiol 107:52–57.  https://doi.org/10.1016/j.yjmcc.2017.05.002 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Hsu PL, Su BC, Kuok QY, Mo FE (2013) Extracellular matrix protein CCN1 regulates cardiomyocyte apoptosis in mice with stress-induced cardiac injury. Cardiovasc Res 98:64–72.  https://doi.org/10.1093/cvr/cvt001 CrossRefPubMedGoogle Scholar
  23. 23.
    Jeyaraman M, Tanguy S, Fandrich RR, Lukas A, Kardami E (2003) Ischemia-induced dephosphorylation of cardiomyocyte connexin-43 is reduced by okadaic acid and calyculin A but not fostriecin. Mol Cell Biochem 242:129–134CrossRefGoogle Scholar
  24. 24.
    Jeyaraman MM, Srisakuldee W, Nicke BE, Kardami E (2012) Connexin43 phosphorylation and cytoprotection in the heart. Biochimica et Biophysica Acta 18:2009–2013.  https://doi.org/10.1016/j.bbamem.2011.06.023 CrossRefGoogle Scholar
  25. 25.
    Kang M, Na Lin, Chen Li, Meng Q, Zheng Y, Yan X, Deng J, Ou Y, Zhang C, He J, Luo D (2014) Cx43 phosphorylation on S279/282 and intercellular communication are regulated by IP3/IP3 receptor signaling. Cell Commun Signal 12:58.  https://doi.org/10.1186/s12964-014-0058-6 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Koyama T, Temma K, Akera T (1991) Reperfusion-induced contracture develops with a decreasing [Ca2+]i in single heart cells. Am J Physiol 261:H1115–H1122.  https://doi.org/10.1152/ajpheart.1991.261.4.H1115 CrossRefPubMedGoogle Scholar
  27. 27.
    Lampe PD, Cooper CD, King TJ, Burt JM (2006) Analysis of Connexin43 phosphorylated at S325, S328 and S330 in normoxic and ischemic heart. J Cell Sci 119:3435–3442.  https://doi.org/10.1242/jcs.03089 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Li X, Heinzel FR, Boengler K, Schulz R, Heusch G (2004) Role of connexin 43 in ischemic preconditioning does not involve intercellular communication through gap junctions. J Mol Cell Cardiol 36:161–163CrossRefGoogle Scholar
  29. 29.
    Lübkemeier I, Requardt RP, Lin X, Sasse P, Andrié R, Schrickel JW, Chkourko H, Bukauskas FF, Kim JS, Frank M, Malan D, Zhang J, Wirth A, Dobrowolski R, Mohler PJ, Offermanns S, Fleischmann BK, Delmar M, Willecke K (2013) Deletion of the last five C-terminal amino acid residues of connexin43 leads to lethal ventricular arrhythmias in mice without affecting coupling via gap junction channels. Basic Res Cardiol 108:348.  https://doi.org/10.1007/s00395-013-0348-y CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Luo D, Yang D, Lan X, Li K, Li X, Chen J, Zhang Y, Xiao RP, Han Q, Cheng H (2008) Nuclear Ca2+ sparks and waves mediated by IP3 receptors in neonatal rat cardiomyocytes. Cell Calcium 43:165–174.  https://doi.org/10.1016/j.ceca.2007.04.017 CrossRefPubMedGoogle Scholar
  31. 31.
    Maguy A, Le Bouter S, Comtois P, Chartier D, Villeneuve L, Wakili R, Nishida K, Nattel S (2009) Ion channel subunit expression changes in cardiac Purkinje fibers: a potential role in conduction abnormalities associated with congestive heart failure. Circ Res 104:1113–1122.  https://doi.org/10.1161/CIRCRESAHA.108.191809 CrossRefPubMedGoogle Scholar
  32. 32.
    Martin ED, Bassi R, Marber MS (2015) p38 in cardioprotection—are we there yet? Br J Pharmacol 172:2101–2113.  https://doi.org/10.1111/bph.12901 CrossRefPubMedGoogle Scholar
  33. 33.
    Miro-Casas E, Ruiz-Meana M, Agullo E, Stahlhofen S, Rodríguez-Sinovas A, Cabestrero A, Jorge I, Torre I, Vazquez J, Boengler K, Schulz R, Heusch G, Garcia-Dorado D (2009) Connexin43 in cardiomyocyte mitochondria contributes to mitochondrial potassium uptake. Cardiovasc Res 83:747–756.  https://doi.org/10.1093/cvr/cvp157 CrossRefPubMedGoogle Scholar
  34. 34.
    Miura T, Ohnuma Y, Kuno A, Tanno M, Ichikawa Y, Nakamura Y, Yano T, Miki T, Sakamoto J, Shimamoto K (2004) Protective role of gap junctions in preconditioning against myocardial infarction. Am J Physiol Heart Circ Physiol 286:H214–H221.  https://doi.org/10.1152/ajpheart.00441.2003 CrossRefPubMedGoogle Scholar
  35. 35.
    Mollenhauer M, Friedrichs K, Lange M, Gesenberg J, Remane L, Kerkenpaβ C, Krause J, Schneider J, Ravekes T, Maass M, Halbach M, Peinkofer G, Saric T, Mehrkens D, Adam M, Deuschl FG, Lau D, Geertz B, Manchanda K, Eschenhagen T, Kubala L, Rudolph TK, Wu Y, Tang WHW, Hazen SL, Baldus S, Klinke A, Rudolph V (2017) Myeloperoxidase mediates postischemic arrhythmogenic ventricular remodeling. Circ Res 121:56–70.  https://doi.org/10.1161/CIRCRESAHA.117.310870 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Morel S, Christoffersen C, Axelsen LN, Montecucco F, Rochemont V, Fria MA, Mach F, James RW, Naus CC, Chanson M, Lampe PD, Nielsen MS, Nielsen LB, Kwak BR (2016) Sphingosine-1-phosphate reduces ischaemia-reperfusion injury by phosphorylating the gap junction protein Connexin43. Cardiovasc Res 109:385–396.  https://doi.org/10.1093/cvr/cvw004 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    O’Quinn MP, Palatinus JA, Harris BS, Hewett KW, Gourdie RG (2011) A peptide mimetic of the connexin43 carboxyl terminus reduces gap junction remodeling and induced arrhythmia following ventricular injury. Circ Res 108:704–715.  https://doi.org/10.1161/CIRCRESAHA.110.235747 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Porras A, Zuluaga S, Black E, Valladares A, Alvarez AM, Ambrosino C, Benito M, Nebreda AR (2004) p38-mitogen-activated protein kinase sensitizes cells to apoptosis induced by different stimuli. Mol Biol Cell 15:922–933.  https://doi.org/10.1091/mbc.E03-08-0592 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Remo BF, Qu J, Volpicelli FM, Giovannone S, Shin D, Lader J, Liu FY, Zhang J, Lent DS, Morley GE, Fishman GI (2011) Phosphatase-resistant gap junctions inhibit pathological remodeling and prevent arrhythmias. Circ Res 108:1459–1466.  https://doi.org/10.1161/CIRCRESAHA.111.244046 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Rose BA, Force T, Wang Y (2010) Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale. Physiol Rev 90:1507–1546.  https://doi.org/10.1152/physrev.00054.2009 CrossRefGoogle Scholar
  41. 41.
    Ruiz-Meana M, Rodríguez-Sinovas A, Cabestrero A, Boengler K, Heusch G, Garcia-Dorado D (2008) Mitochondrial connexin43 as a new player in the pathophysiology of myocardial ischaemia–reperfusion injury. Cardiovasc Res 77:325–333.  https://doi.org/10.1093/cvr/cvm062 CrossRefPubMedGoogle Scholar
  42. 42.
    Saliba Y, Mougenot N, Jacquet A, Atassi F, Hatem S, Farès N, Lompré AM (2012) A new method of ultrasonic nonviral gene delivery to the adult myocardium. J Mol Cell Cardiol 53:801–808.  https://doi.org/10.1016/j.yjmcc.2012.07.016 CrossRefPubMedGoogle Scholar
  43. 43.
    Schreiber T, Salhöfer L, Quinting T, Fandrey J (2019) Things get broken: the hypoxia-inducible factor prolyl hydroxylases in ischemic heart disease. Basic Res Cardiol 114:16.  https://doi.org/10.1007/s00395-019-0725-2 CrossRefPubMedGoogle Scholar
  44. 44.
    Schrickel JW, Lickfett L, Lewalter T, Tiemann K, Nickenig G, Baba H, Heusch G, Schulz R, Levkau B (2012) Cardiomyocyte-specific deletion of survivin causes global cardiac conduction defects. Basic Res Cardiol 107:299.  https://doi.org/10.1007/s00395-012-0299-8 CrossRefPubMedGoogle Scholar
  45. 45.
    Schulz R, Görge PM, Görbe A, Ferdinandy P, Lampe PD, Leybaert L (2015) Connexin43 is an emerging therapeutic target in ischemia/reperfusion injury, cardioprotection and neuroprotection. Pharmacol Ther 153:90–106.  https://doi.org/10.1016/j.pharmthera.2015.06.005 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Schulz R, Gres P, Skyschally A, Duschin A, Belosjorow S, Konietzka I, Heusch G (2003) Ischemic preconditioning preserves connexin 43 phosphorylation during sustained ischemia in pig hearts in vivo. FASEB J 17:1355–1357CrossRefGoogle Scholar
  47. 47.
    Skyschally A, Walter B, Schultz R, Heusch G (2013) The antiarrhythmic dipeptide ZP1609 (danegaptide) when given at reperfusion reduces myocardial infarct size in pigs. Naunyn-Schmiedeberg’s Arch Pharmacol 386:383–391.  https://doi.org/10.1007/s00210-013-0840-9 CrossRefGoogle Scholar
  48. 48.
    Smyth JW, Hong TT, Gao D, Vogan JM, Jensen BC, Fong TS, Simpson PC, Stainier DY, Chi NC, Shaw RM (2010) Limited forward trafficking of connexin 43 reduces cell-cell coupling in stressed human and mouse myocardium. J Clin Invest 120:266–279.  https://doi.org/10.1172/JCI39740 CrossRefPubMedGoogle Scholar
  49. 49.
    Solan JL, Lampe PD (2009) Connexin43 phosphorylation: structural changes and biological effects. Biochem J 419:261–272.  https://doi.org/10.1042/BJ20082319 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Solan JL, Lampe PD (2018) Spatio-temporal regulation of connexin43 phosphorylation and gap junction dynamics. Biochim Biophys Acta Biomembr 1860:83–90.  https://doi.org/10.1016/j.bbamem.2017.04.008 CrossRefPubMedGoogle Scholar
  51. 51.
    Solan JL, Marquez-Rosado L, Sorgen PL, Thornton PJ, Gafken PR, Lampe PD (2007) Phosphorylation of Cx43 at S365 is a gatekeeper event that changes the structure of Cx43 and prevents downregulation by PKC. J Cell Biol 179:1301–1309.  https://doi.org/10.1083/jcb.200707060 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Srisakuldee W, Jeyaraman MM, Nickel BE, Tanguy S, Jiang ZS, Kardami E (2009) Phosphorylation of connexin43 at serine 262 promotes a cardiac injury-resistant state. Cardiovasc Res 83:672–681.  https://doi.org/10.1093/cvr/cvp142 CrossRefPubMedGoogle Scholar
  53. 53.
    Sun Z, Yang Y, Wu L, Talabieke S, You H, Zheng Y, Luo D (2019) Connexin 43-serine 282 modulates serine 279 phosphorylation in cardiomyocytes. Biochem Biophys Res Commun 513:567–572.  https://doi.org/10.1016/j.bbrc.2019.04.032 CrossRefPubMedGoogle Scholar
  54. 54.
    Tribulová N, Knezl V, Okruhlicová L, Slezák J (2008) Myocardial gap junctions: targets for novel approaches in the prevention of life-threatening cardiac arrhythmias. Physiol Res 57(Suppl 2):S1–S13PubMedGoogle Scholar
  55. 55.
    Wang N, De Vuyst E, Ponsaerts R, Boengler K, Palacios-Prado N, Wauman J, Lai CP, De Bock M, Decrock E, Bol M, Vinken M, Rogiers V, Tavernier J, Evans WH, Naus CC, Bukauskas FF, Sipido KR, Heusch G, Schulz R, Bultynck G, Leybaert L (2013) Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury. Basic Res Cardiol 108:309.  https://doi.org/10.1007/s00395-012-0309-x CrossRefPubMedGoogle Scholar
  56. 56.
    Weinbrenner C, Baines CP, Liu GD, Armstrong SC, Ganote CE, Walsh AH, Honkanen RE, Cohen MV, Downey JM (1998) Fostriecin, an inhibitor of protein phosphatase 2A, limits myocardial infarct size even when administered after onset of ischemia. Circulation 98:899–905.  https://doi.org/10.1161/01.CIR.96.10.3579 CrossRefPubMedGoogle Scholar
  57. 57.
    Yang Y, Yan X, Xue J, Zheng Y, Chen M, Sun Z, Liu T, Wang C, You H, Luo D (2019) Connexin43 dephosphorylation at serine 282 is associated with connexin43-mediated cardiomyocyte apoptosis. Cell Death Differ 26:1332–1345.  https://doi.org/10.1038/s41418-019-0277-x CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Jingyi Xue
    • 1
  • Xinxin Yan
    • 1
    • 2
  • Yutong Yang
    • 1
  • Min Chen
    • 1
  • Lulin Wu
    • 1
  • Zhongshan Gou
    • 1
    • 2
  • Zhipeng Sun
    • 1
  • Shaletanati Talabieke
    • 1
  • Yuanyuan Zheng
    • 1
  • Dali Luo
    • 1
    Email author
  1. 1.Department of Pharmacology, Beijing Key Laboratory of Metabolic Disturbance Related Cardiovascular Disease, School of Basic Medical SciencesCapital Medical UniversityBeijingPeople’s Republic of China
  2. 2.The Affiliated Suzhou Hospital of Nanjing Medical UniversitySuzhouPeople’s Republic of China

Personalised recommendations