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The different response of cardiomyocytes and cardiac fibroblasts to mitochondria inhibition and the underlying role of STAT3

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Abstract

Cardiomyocyte loss and cardiac fibrosis are the main characteristics of cardiac ischemia and heart failure, and mitochondrial function of cardiomyocytes is impaired in cardiac ischemia and heart failure, so the aim of this study is to identify fate variability of cardiomyocytes and cardiac fibroblasts with mitochondria inhibition and explore the underlying mechanism. The mitochondrial respiratory function was measured by using Oxygraph-2k high-resolution respirometry. The STAT3 expression and activity were evaluated by western blot. Cardiomyocytes and cardiac fibroblasts displayed different morphology. The mitochondrial respiratory function and the expressions of mitochondrial complex I, II, III, IV, and V of cardiac fibroblasts were lower than that of cardiomyocytes. Mitochondrial respiratory complex I inhibitor rotenone and H2O2 (100 µM, 4 h) treatment induced cell death of cardiomyocyte but not cardiac fibroblasts. The function of complex I/II was impaired in cardiomycytes but not cardiac fibroblasts stimulated with H2O2 (100 µM, 4 h) and in ischemic heart of mice. Rotenone and H2O2 (100 µM, 4 h) treatment reduced STAT3 expression and activity in cardiomyocytes but not cardiac fibroblasts. Inhibition of STAT3 impaired mitochondrial respiratory capacity and exacerbated H2O2-induced cell injury in cardiomycytes but not significantly in cardiac fibroblasts. In conclusion, the different susceptibility of cardiomyocytes and cardiac fibroblasts to mitochondria inhibition determines the cell fate under the same pathological stimuli and in which STAT3 plays a critical role.

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References

  1. Boengler K, Ungefug E, Heusch G, Schulz R (2013) The STAT3 inhibitor stattic impairs cardiomyocyte mitochondrial function through increased reactive oxygen species formation. Curr Pharm Des 19:6890–6895

    Article  CAS  Google Scholar 

  2. Bolli R, Stein AB, Guo Y, Wang OL, Rokosh G, Dawn B, Molkentin JD, Sanganalmath SK, Zhu Y, Xuan YT (2011) A murine model of inducible, cardiac-specific deletion of STAT3: its use to determine the role of STAT3 in the upregulation of cardioprotective proteins by ischemic preconditioning. J Mol Cell Cardiol 50:589–597. https://doi.org/10.1016/j.yjmcc.2011.01.002

    Article  CAS  Google Scholar 

  3. Carbognin E, Betto RM, Soriano ME, Smith AG, Martello G (2016) Stat3 promotes mitochondrial transcription and oxidative respiration during maintenance and induction of naive pluripotency. EMBO J 35:618–634. https://doi.org/10.15252/embj.201592629

    Article  CAS  Google Scholar 

  4. Coronado M, Fajardo G, Nguyen K, Zhao M, Kooiker K, Jung G, Hu DQ, Reddy S, Sandoval E, Stotland A, Gottlieb RA, Bernstein D (2018) Physiological mitochondrial fragmentation is a normal cardiac adaptation to increased energy demand. Circ Res 122:282–295. https://doi.org/10.1161/CIRCRESAHA.117.310725

    Article  CAS  Google Scholar 

  5. Cui YC, Yan L, Pan CS, Hu BH, Chang X, Fan JY, Han JY (2018) The contribution of different components in QiShenYiQi Pills(R) to its potential to modulate energy metabolism in protection of ischemic myocardial injury. Front Physiol 9:389. https://doi.org/10.3389/fphys.2018.00389

    Article  Google Scholar 

  6. Datta R, Bansal T, Rana S, Datta K, Datta Chaudhuri R, Chawla-Sarkar M, Sarkar S (2017) Myocyte-derived Hsp90 modulates collagen upregulation via biphasic activation of STAT-3 in fibroblasts during cardiac hypertrophy. Mol Cell Biol 37:e00611–e00616. https://doi.org/10.1128/MCB.00611-16

    Article  CAS  Google Scholar 

  7. Dhingra R, Margulets V, Chowdhury SR, Thliveris J, Jassal D, Fernyhough P, Dorn GW 2nd, Kirshenbaum LA (2014) Bnip3 mediates doxorubicin-induced cardiac myocyte necrosis and mortality through changes in mitochondrial signaling. Proc Natl Acad Sci USA 111:E5537–E5544. https://doi.org/10.1073/pnas.1414665111

    Article  CAS  Google Scholar 

  8. Galan DT, Bito V, Claus P, Holemans P, Abi-Char J, Nagaraju CK, Dries E, Vermeulen K, Ventura-Clapier R, Sipido KR, Driesen RB (2016) Reduced mitochondrial respiration in the ischemic as well as in the remote nonischemic region in postmyocardial infarction remodeling. Am J Physiol Heart Circ Physiol 311:H1075–H1090. https://doi.org/10.1152/ajpheart.00945.2015

    Article  Google Scholar 

  9. Galdos FX, Guo Y, Paige SL, VanDusen NJ, Wu SM, Pu WT (2017) Cardiac regeneration: lessons from development. Circ Res 120:941–959. https://doi.org/10.1161/CIRCRESAHA.116.309040

    Article  CAS  Google Scholar 

  10. Gao JL, Zhao J, Zhu HB, Peng X, Zhu JX, Ma MH, Fu Y, Hu N, Tai Y, Xuan XC, Dong DL (2018) Characterizations of mitochondrial uncoupling induced by chemical mitochondrial uncouplers in cardiomyocytes. Free Radic Biol Med 124:288–298. https://doi.org/10.1016/j.freeradbiomed.2018.06.020

    Article  CAS  Google Scholar 

  11. Gent S, Skyschally A, Kleinbongard P, Heusch G (2017) lschemic preconditioning in pigs: a causal role for signal transducer and activator of transcription 3. Am J Physiol Heart Circ Physiol 312:H478–H484. https://doi.org/10.1152/ajpheart.00749.2016

    Article  Google Scholar 

  12. Goldenthal MJ (2016) Mitochondrial involvement in myocyte death and heart failure. Heart Fail Rev 21:137–155. https://doi.org/10.1007/s10741-016-9531-1

    Article  CAS  Google Scholar 

  13. Haghikia A, Ricke-Hoch M, Stapel B, Gorst I, Hilfiker-Kleiner D (2014) STAT3, a key regulator of cell-to-cell communication in the heart. Cardiovasc Res 102:281–289. https://doi.org/10.1093/cvr/cvu034

    Article  CAS  Google Scholar 

  14. Heusch G, Musiolik J, Gedik N, Skyschally A (2011) Mitochondrial STAT3 activation and cardioprotection by ischemic postconditioning in pigs with regional myocardial ischemia/reperfusion. Circ Res 109:1302–1308. https://doi.org/10.1161/CIRCRESAHA.111.255604

    Article  CAS  Google Scholar 

  15. Hilfiker-Kleiner D, Hilfiker A, Fuchs M, Kaminski K, Schaefer A, Schieffer B, Hillmer A, Schmiedl A, Ding Z, Podewski E, Podewski E, Poli V, Schneider MD, Schulz R, Park JK, Wollert KC, Drexler H (2004) Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition, and heart protection from ischemic injury. Circ Res 95:187–195. https://doi.org/10.1161/01.RES.0000134921.50377.61

    Article  CAS  Google Scholar 

  16. Huang CH, Tsai MS, Chiang CY, Su YJ, Wang TD, Chang WT, Chen HW, Chen WJ (2015) Activation of mitochondrial STAT-3 and reduced mitochondria damage during hypothermia treatment for post-cardiac arrest myocardial dysfunction. Basic Res Cardiol 110:59. https://doi.org/10.1007/s00395-015-0516-3

    Article  CAS  Google Scholar 

  17. Huang Z, Chen XJ, Qian C, Dong Q, Ding D, Wu QF, Li J, Wang HF, Li WH, Xie Q, Cheng X, Zhao N, Du YM, Liao YH (2016) Signal transducer and activator of transcription 3/MicroRNA-21 feedback loop contributes to atrial fibrillation by promoting atrial fibrosis in a rat sterile pericarditis model. Circ Arrhythm Electrophysiol 9:e003396. https://doi.org/10.1161/CIRCEP.115.003396

    Article  Google Scholar 

  18. Kan J, Guo W, Huang C, Bao G, Zhu Y, Zhu YZ (2014) S-propargyl-cysteine, a novel water-soluble modulator of endogenous hydrogen sulfide, promotes angiogenesis through activation of signal transducer and activator of transcription 3. Antioxid Redox Signal 20:2303–2316. https://doi.org/10.1089/ars.2013.5449

    Article  CAS  Google Scholar 

  19. Kanamori H, Takemura G, Goto K, Maruyama R, Ono K, Nagao K, Tsujimoto A, Ogino A, Takeyama T, Kawaguchi T, Watanabe T, Kawasaki M, Fujiwara T, Fujiwara H, Seishima M, Minatoguchi S (2011) Autophagy limits acute myocardial infarction induced by permanent coronary artery occlusion. Am J Physiol Heart Circ Physiol 300:H2261–H2271. https://doi.org/10.1152/ajpheart.01056.2010

    Article  CAS  Google Scholar 

  20. Kleinbongard P, Skyschally A, Gent S, Pesch M, Heusch G (2017) STAT3 as a common signal of ischemic conditioning: a lesson on “rigor and reproducibility” in preclinical studies on cardioprotection. Basic Res Cardiol 113:3. https://doi.org/10.1007/s00395-017-0660-z

    Article  CAS  Google Scholar 

  21. Lacraz GPA, Junker JP, Gladka MM, Molenaar B, Scholman KT, Vigil-Garcia M, Versteeg D, de Ruiter H, Vermunt MW, Creyghton MP, Huibers MMH, de Jonge N, van Oudenaarden A, van Rooij E (2017) Tomo-Seq identifies SOX9 as a key regulator of cardiac fibrosis during ischemic injury. Circulation 136:1396–1409. https://doi.org/10.1161/CIRCULATIONAHA.117.027832

    Article  CAS  Google Scholar 

  22. Lew M (2007) Good statistical practice in pharmacology. Problem 2. Br J Pharmacol 152:299–303. https://doi.org/10.1038/sj.bjp.0707372

    Article  CAS  Google Scholar 

  23. Liu H, Shao Y, Qin W, Runyan RB, Xu M, Ma Z, Borg TK, Markwald R, Gao BZ (2013) Myosin filament assembly onto myofibrils in live neonatal cardiomyocytes observed by TPEF-SHG microscopy. Cardiovasc Res 97:262–270. https://doi.org/10.1093/cvr/cvs328

    Article  CAS  Google Scholar 

  24. Liu MY, Jin J, Li SL, Yan J, Zhen CL, Gao JL, Zhang YH, Zhang YQ, Shen X, Zhang LS, Wei YY, Zhao Y, Wang CG, Bai YL, Dong DL (2016) Mitochondrial fission of smooth muscle cells is involved in artery constriction. Hypertension 68:1245–1254. https://doi.org/10.1161/HYPERTENSIONAHA.116.07974

    Article  CAS  Google Scholar 

  25. Matsuda T, Zhai P, Sciarretta S, Zhang Y, Jeong JI, Ikeda S, Park J, Hsu CP, Tian B, Pan D, Sadoshima J, Del Re DP (2016) NF2 activates hippo signaling and promotes ischemia/reperfusion injury in the heart. Circ Res 119:596–606. https://doi.org/10.1161/CIRCRESAHA.116.308586

    Article  CAS  Google Scholar 

  26. Mukaddim RA, Rodgers A, Hacker TA, Heinmiller A, Varghese T (2018) Real-time in vivo photoacoustic imaging in the assessment of myocardial dynamics in murine model of myocardial ischemia. Ultrasound Med Biol 44:2155–2164. https://doi.org/10.1016/j.ultrasmedbio.2018.05.021

    Article  Google Scholar 

  27. Müller J, Gorressen S, Grandoch M, Feldmann K, Kretschmer I, Lehr S, Ding Z, Schmitt JP, Schrader J, Garbers C, Heusch G, Kelm M, Scheller J, Fischer JW (2014) Interleukin-6-dependent phenotypic modulation of cardiac fibroblasts after acute myocardial infarction. Basic Res Cardiol 109:440. https://doi.org/10.1007/s00395-014-0440-y

    Article  CAS  Google Scholar 

  28. Nguyen BY, Ruiz-Velasco A, Bui T, Collins L, Wang X, Liu W (2018) Mitochondrial function in the heart: the insight into mechanisms and therapeutic potentials. Br J Pharmacol. https://doi.org/10.1111/bph.14431

    Article  Google Scholar 

  29. Nielsen SH, Mouton AJ, DeLeon-Pennell KY, Genovese F, Karsdal M, Lindsey ML (2017) Understanding cardiac extracellular matrix remodeling to develop biomarkers of myocardial infarction outcomes. Matrix Biol. https://doi.org/10.1016/j.matbio.2017.12.001

    Article  Google Scholar 

  30. O’Sullivan KE, Breen EP, Gallagher HC, Buggy DJ, Hurley JP (2016) Understanding STAT3 signaling in cardiac ischemia. Basic Res Cardiol 111:27. https://doi.org/10.1007/s00395-016-0543-8

    Article  CAS  Google Scholar 

  31. Paradies G, Petrosillo G, Pistolese M, Di Venosa N, Federici A, Ruggiero FM (2004) Decrease in mitochondrial complex I activity in ischemic/reperfused rat heart: involvement of reactive oxygen species and cardiolipin. Circ Res 94:53–59. https://doi.org/10.1161/01.RES.0000109416.56608.64

    Article  CAS  Google Scholar 

  32. Pedrotty DM, Klinger RY, Kirkton RD, Bursac N (2009) Cardiac fibroblast paracrine factors alter impulse conduction and ion channel expression of neonatal rat cardiomyocytes. Cardiovasc Res 83:688–697. https://doi.org/10.1093/cvr/cvp164

    Article  CAS  Google Scholar 

  33. Schipper DA, Palsma R, Marsh KM, O’Hare C, Dicken DS, Lick S, Kazui T, Johnson K, Smolenski RT, Duncker DJ, Khalpey Z (2017) Chronic myocardial ischemia leads to loss of maximal oxygen consumption and complex I dysfunction. Ann Thorac Surg 104:1298–1304. https://doi.org/10.1016/j.athoracsur.2017.03.004

    Article  Google Scholar 

  34. Schirone L, Forte M, Palmerio S, Yee D, Nocella C, Angelini F, Pagano F, Schiavon S, Bordin A, Carrizzo A, Vecchione C, Valenti V, Chimenti I, De Falco E, Sciarretta S, Frati G (2017) A review of the molecular mechanisms underlying the development and progression of cardiac remodeling. Oxid Med Cell Longev 2017:3920195. https://doi.org/10.1155/2017/3920195

    Article  CAS  Google Scholar 

  35. Stapel B, Kohlhaas M, Ricke-Hoch M, Haghikia A, Erschow S, Knuuti J, Silvola JM, Roivainen A, Saraste A, Nickel AG, Saar JA, Sieve I, Pietzsch S, Muller M, Bogeski I, Kappl R, Jauhiainen M, Thackeray JT, Scherr M, Bengel FM, Hagl C, Tudorache I, Bauersachs J, Maack C, Hilfiker-Kleiner D (2017) Low STAT3 expression sensitizes to toxic effects of beta-adrenergic receptor stimulation in peripartum cardiomyopathy. Eur Heart J 38:349–361. https://doi.org/10.1093/eurheartj/ehw086

    Article  CAS  Google Scholar 

  36. Su SA, Yang D, Wu Y, Xie Y, Zhu W, Cai Z, Shen J, Fu Z, Wang Y, Jia L, Wang Y, Wang JA, Xiang M (2017) EphrinB2 regulates cardiac fibrosis through modulating the interaction of Stat3 and TGF-beta/Smad3 signaling. Circ Res 121:617–627. https://doi.org/10.1161/CIRCRESAHA.117.311045

    Article  CAS  Google Scholar 

  37. Sun B, Huo R, Sheng Y, Li Y, Xie X, Chen C, Liu HB, Li N, Li CB, Guo WT, Zhu JX, Yang BF, Dong DL (2013) Bone morphogenetic protein-4 mediates cardiac hypertrophy, apoptosis, and fibrosis in experimentally pathological cardiac hypertrophy. Hypertension 61:352–360. https://doi.org/10.1161/HYPERTENSIONAHA.111.00562

    Article  CAS  Google Scholar 

  38. Szczepanek K, Chen Q, Larner AC, Lesnefsky EJ (2012) Cytoprotection by the modulation of mitochondrial electron transport chain: the emerging role of mitochondrial STAT3. Mitochondrion 12:180–189. https://doi.org/10.1016/j.mito.2011.08.011

    Article  CAS  Google Scholar 

  39. Szczepanek K, Xu A, Hu Y, Thompson J, He J, Larner AC, Salloum FN, Chen Q, Lesnefsky EJ (2015) Cardioprotective function of mitochondrial-targeted and transcriptionally inactive STAT3 against ischemia and reperfusion injury. Basic Res Cardiol 110:53. https://doi.org/10.1007/s00395-015-0509-2

    Article  CAS  Google Scholar 

  40. Wang JX, Zhang XJ, Li Q, Wang K, Wang Y, Jiao JQ, Feng C, Teng S, Zhou LY, Gong Y, Zhou ZX, Liu J, Wang JL, Li PF (2015) MicroRNA-103/107 regulate programmed necrosis and myocardial ischemia/reperfusion injury through targeting FADD. Circ Res 117:352–363. https://doi.org/10.1161/CIRCRESAHA.117.305781

    Article  CAS  Google Scholar 

  41. Wegrzyn J, Potla R, Chwae YJ, Sepuri NB, Zhang Q, Koeck T, Derecka M, Szczepanek K, Szelag M, Gornicka A, Moh A, Moghaddas S, Chen Q, Bobbili S, Cichy J, Dulak J, Baker DP, Wolfman A, Stuehr D, Hassan MO, Fu XY, Avadhani N, Drake JI, Fawcett P, Lesnefsky EJ, Larner AC (2009) Function of mitochondrial Stat3 in cellular respiration. Science 323:793–797. https://doi.org/10.1126/science.1164551

    Article  CAS  Google Scholar 

  42. Wust RC, de Vries HJ, Wintjes LT, Rodenburg RJ, Niessen HW, Stienen GJ (2016) Mitochondrial complex I dysfunction and altered NAD(P)H kinetics in rat myocardium in cardiac right ventricular hypertrophy and failure. Cardiovasc Res 111:362–372. https://doi.org/10.1093/cvr/cvw176

    Article  CAS  Google Scholar 

  43. Xiao XL, Hu N, Zhang XZ, Jiang M, Chen C, Ma R, Ma ZG, Gao JL, Xuan XC, Sun ZJ, Dong DL (2018) Niclosamide inhibits vascular smooth muscle cell proliferation, migration, and attenuates neointimal hyperplasia in injured rat carotid arteries. Br J Pharmacol 175:1707–1718. https://doi.org/10.1111/bph.14182

    Article  CAS  Google Scholar 

  44. Xie X, Zhao Y, Ma CY, Xu XM, Zhang YQ, Wang CG, Jin J, Shen X, Gao JL, Li N, Sun ZJ, Dong DL (2015) Dimethyl fumarate induces necroptosis in colon cancer cells through GSH depletion/ROS increase/MAPKs activation pathway. Br J Pharmacol 172:3929–3943. https://doi.org/10.1111/bph.13184

    Article  CAS  Google Scholar 

  45. Xiong S, Wang P, Ma L, Gao P, Gong L, Li L, Li Q, Sun F, Zhou X, He H, Chen J, Yan Z, Liu D, Zhu Z (2016) Ameliorating endothelial mitochondrial dysfunction restores coronary function via transient receptor potential vanilloid 1-mediated protein kinase A/uncoupling protein 2 pathway. Hypertension 67:451–460. https://doi.org/10.1161/HYPERTENSIONAHA.115.06223

    Article  CAS  Google Scholar 

  46. Zouein FA, Altara R, Chen Q, Lesnefsky EJ, Kurdi M, Booz GW (2015) Pivotal importance of STAT3 in protecting the heart from acute and chronic stress: new advancement and unresolved issues. Front Cardiovasc Med 2:36. https://doi.org/10.3389/fcvm.2015.00036

    Article  CAS  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (Nos. 81773725, 91739102).

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  1. Jing Zhao and Jin-Lai Gao contributed equally to the work.

Authors and Affiliations

  1. Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Baojian Road 157, Harbin, 150086, People’s Republic of China

    Jing Zhao, Jin-Lai Gao, Jun-Xue Zhu, Hai-Bin Zhu, Xuan Peng, Man Jiang, Yao Fu, Juan Xu, Xi-Hai Mao, Nan Hu, Ming-Hui Ma & De-Li Dong

  2. Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, People’s Republic of China

    Jing Zhao, Jin-Lai Gao, Jun-Xue Zhu, Hai-Bin Zhu, Xuan Peng, Man Jiang, Yao Fu, Juan Xu, Xi-Hai Mao, Nan Hu, Ming-Hui Ma & De-Li Dong

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  1. Jing Zhao
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Zhao, J., Gao, JL., Zhu, JX. et al. The different response of cardiomyocytes and cardiac fibroblasts to mitochondria inhibition and the underlying role of STAT3. Basic Res Cardiol 114, 12 (2019). https://doi.org/10.1007/s00395-019-0721-6

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