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ZAK induces cardiomyocyte hypertrophy and brain natriuretic peptide expression via p38/JNK signaling and GATA4/c-Jun transcriptional factor activation

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Abstract

Cardiomyocyte hypertrophy is an adaptive response of heart to various stress conditions. During the period of stress accumulation, transition from physiological hypertrophy to pathological hypertrophy results in the promotion of heart failure. Our previous studies found that ZAK, a sterile alpha motif and leucine zipper containing kinase, was highly expressed in infarcted human hearts and demonstrated that overexpression of ZAK induced cardiac hypertrophy. This study evaluates, cellular events associated with the expression of two doxycycline (Dox) inducible Tet-on ZAK expression systems, a Tet-on ZAK WT (wild-type), and a Tet-on ZAK DN (mutant, Dominant-negative form) in H9c2 myoblast cells; Tet-on ZAK WT was found to increase cell size and hypertrophic marker BNP in a dose-dependent manner. To ascertain the mechanism of ZAK-mediated hypertrophy, expression analysis with various inhibitors of the related upstream and downstream proteins was performed. Tet-on ZAK WT expression triggered the p38 and JNK pathway and also activated the expression and nuclear translocation of p-GATA4 and p-c-Jun transcription factors, without the involvement of p-ERK or NFATc3. However, Tet-on ZAK DN showed no effect on the p38 and JNK signaling cascade. The results showed that the inhibitors of JNK1/2 and p38 significantly suppressed ZAK-induced BNP expression. The results show the role of ZAK and/or the ZAK downstream events such as JNK and p38 phosphorylation, c-Jun, and GATA-4 nuclear translocation in cardiac hypertrophy. ZAK and/or the ZAK downstream p38, and JNK pathway could therefore be potential targets to ameliorate cardiac hypertrophy symptoms in ZAK-overexpressed patients.

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References

  1. Maurer MS, Kronzon I, Burkhoff D (2006) Ventricular pump function in heart failure with normal ejection fraction: insights from pressure-volume measurements. Prog Cardiovasc Dis 49:182–195. doi:10.1016/j.pcad.2006.08.007

    Article  PubMed  Google Scholar 

  2. Aiello VD, Binotto MA (2007) Myocardial remodeling in congenital heart disease. Arq Bras Cardiol 88:e185–e186

    Article  PubMed  Google Scholar 

  3. Lorell BH, Carabello BA (2000) Left ventricular hypertrophy: pathogenesis, detection, and prognosis. Circulation 102:470–479

    Article  CAS  PubMed  Google Scholar 

  4. Marian AJ, Roberts R (1995) Recent advances in the molecular genetics of hypertrophic cardiomyopathy. Circulation 92:1336–1347

    Article  CAS  PubMed  Google Scholar 

  5. Hunter JJ, Chien KR (1999) Signaling pathways for cardiac hypertrophy and failure. N Engl J Med 341:1276–1283. doi:10.1056/NEJM199910213411706

    Article  CAS  PubMed  Google Scholar 

  6. Opie LH, Commerford PJ, Gersh BJ, Pfeffer MA (2006) Controversies in ventricular remodelling. Lancet 367:356–367. doi:10.1016/S0140-6736(06)68074-4

    Article  PubMed  Google Scholar 

  7. Sugden PH, Clerk A (1998) Cellular mechanisms of cardiac hypertrophy. J Mol Med 76:725–746

    Article  CAS  PubMed  Google Scholar 

  8. Chien KR, Knowlton KU, Zhu H, Chien S (1991) Regulation of cardiac gene expression during myocardial growth and hypertrophy: molecular studies of an adaptive physiologic response. FASEB J 5:3037–3046

    CAS  PubMed  Google Scholar 

  9. Frey N, Katus HA, Olson EN, Hill JA (2004) Hypertrophy of the heart: a new therapeutic target? Circulation 109:1580–1589. doi:10.1161/01.CIR.0000120390.68287.BB

    Article  PubMed  Google Scholar 

  10. Garrington TP, Johnson GL (1999) Organization and regulation of mitogen-activated protein kinase signaling pathways. Curr Opin Cell Biol 11:211–218

    Article  CAS  PubMed  Google Scholar 

  11. Heineke J, Molkentin JD (2006) Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol 7:589–600. doi:10.1038/nrm1983

    Article  CAS  PubMed  Google Scholar 

  12. Tenhunen O, Sarman B, Kerkela R, Szokodi I, Papp L, Toth M, Ruskoaho H (2004) Mitogen-activated protein kinases p38 and ERK 1/2 mediate the wall stress-induced activation of GATA-4 binding in adult heart. J Biol Chem 279:24852–24860. doi:10.1074/jbc.M31

    Article  CAS  PubMed  Google Scholar 

  13. Kerkela R, Pikkarainen S, Majalahti-Palviainen T, Tokola H, Ruskoaho H (2002) Distinct roles of mitogen-activated protein kinase pathways in GATA-4 transcription factor-mediated regulation of B-type natriuretic peptide gene. J Biol Chem 277:13752–13760. doi:10.1074/jbc.M105

    Article  CAS  PubMed  Google Scholar 

  14. Komuro I, Yazaki Y (1993) Control of cardiac gene expression by mechanical stress. Annu Rev Physiol 55:55–75. doi:10.1146/annurev.ph.55.030193.000415

    Article  CAS  PubMed  Google Scholar 

  15. Sadoshima J, Izumo S (1997) The cellular and molecular response of cardiac myocytes to mechanical stress. Annu Rev Physiol 59:551–571. doi:10.1146/annurev.physiol.59.1.551

    Article  CAS  PubMed  Google Scholar 

  16. Liu TC, Huang CJ, Chu YC, Wei CC, Chou CC, Chou MY, Chou CK, Yang JJ (2000) Cloning and expression of ZAK, a mixed lineage kinase-like protein containing a leucine-zipper and a sterile-alpha motif. Biochem Biophys Res Commun 274:811–816. doi:10.1006/bbrc.2000.3236

    Article  CAS  PubMed  Google Scholar 

  17. Gallo KA, Johnson GL (2002) Mixed-lineage kinase control of JNK and p38 MAPK pathways. Nat Rev Mol Cell Biol 3:663–672. doi:10.1038/nrm906

    Article  CAS  PubMed  Google Scholar 

  18. Fanger GR, Gerwins P, Widmann C, Jarpe MB, Johnson GL (1997) MEKKs, GCKs, MLKs, PAKs, TAKs, and tpls: upstream regulators of the c-Jun amino-terminal kinases? Curr Opin Genet Dev 7:67–74

    Article  CAS  PubMed  Google Scholar 

  19. Yang JJ (2002) Mixed lineage kinase ZAK utilizing MKK7 and not MKK4 to activate the c-Jun N-terminal kinase and playing a role in the cell arrest. Biochem Biochem Biophys Res Commun 297:105–110

    Article  CAS  Google Scholar 

  20. Cheng YC, Kuo WW, Wu HC, Lai TY, Wu CH, Hwang JM, Wang WH, Tsai FJ, Yang JJ, Huang CY, Chu CH (2009) ZAK induces MMP-2 activity via JNK/p38 signals and reduces MMP-9 activity by increasing TIMP-1/2 expression in H9c2 cardiomyoblast cells. Mol Cell Biochem 325:69–77. doi:10.1007/s11010-008-0021-1

    Article  CAS  PubMed  Google Scholar 

  21. Huang CY, Chueh PJ, Tseng CT, Liu KY, Tsai HY, Kuo WW, Chou MY, Yang JJ (2004) ZAK re-programs atrial natriuretic factor expression and induces hypertrophic growth in H9c2 cardiomyoblast cells. Biochem Biophys Res Commun 324:973–980. doi:10.1016/j.bbrc.2004.09.156

    Article  CAS  PubMed  Google Scholar 

  22. Huang CY, Kuo WW, Chueh PJ, Tseng CT, Chou MY, Yang JJ (2004) Transforming growth factor-beta induces the expression of ANF and hypertrophic growth in cultured cardiomyoblast cells through ZAK. Biochem Biophys Res Commun 324:424–431. doi:10.1016/j.bbrc.2004.09.067

    Article  CAS  PubMed  Google Scholar 

  23. Chang Y-M, Velmurugan BK, Kuo W-W, Chen Y-S, Ho T-J, Tsai C-T, Ye C-X, Tsai C-H, Tsai F-J, Huang C-Y (2013) Inhibitory effect of alpinate Oxyphyllae fructus extracts on Ang II-induced cardiac pathological remodeling-related pathways in H9c2 cardiomyoblast cells. BioMedicine 3:148–152

    Article  Google Scholar 

  24. Towbin JA, Bowles NE (2002) The failing heart. Nature 415:227–233. doi:10.1038/415227a415227a

    Article  CAS  PubMed  Google Scholar 

  25. Nadal-Ginard B, Kajstura J, Anversa P, Leri A (2003) A matter of life and death: cardiac myocyte apoptosis and regeneration. J Clin Invest 111:1457–1459. doi:10.1172/JCI18611

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Nadal-Ginard B, Kajstura J, Leri A, Anversa P (2003) Myocyte death, growth, and regeneration in cardiac hypertrophy and failure. Circ Res 92:139–150

    Article  CAS  PubMed  Google Scholar 

  27. Sugden PH (1999) Signaling in myocardial hypertrophy: life after calcineurin? Circ Res 84:633–646

    Article  CAS  PubMed  Google Scholar 

  28. Liang F, Lu S, Gardner DG (2000) Endothelin-dependent and -independent components of strain-activated brain natriuretic peptide gene transcription require extracellular signal regulated kinase and p38 mitogen-activated protein kinase. Hypertension 35:188–192

    Article  CAS  PubMed  Google Scholar 

  29. Molkentin JD, Lu JR, Antos CL, Markham B, Richardson J, Robbins J, Grant SR, Olson EN (1998) A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93:215–228

    Article  CAS  PubMed  Google Scholar 

  30. Nadruz W Jr, Corat MA, Marin TM, Guimaraes Pereira GA, Franchini KG (2005) Focal adhesion kinase mediates MEF2 and c-Jun activation by stretch: role in the activation of the cardiac hypertrophic genetic program. Cardiovasc Res 68:87–97. doi:10.1016/j.cardiores.2005.05.011

    Article  CAS  PubMed  Google Scholar 

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Acknowledgment

This study was supported financially by the Taiwan Department of Health, Clinical Trial and Research Center of Excellence (MOHW104-TDU-B-212-113002).

Compliance with ethical standards

This article does not contain any studies with human participants performed by any of the authors. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institutional animal care and use committee (IACUC) of China Medical University.

Conflict of interest

No conflict of interest exists to be declared.

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Authors and Affiliations

  1. Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan

    You-Liang Hsieh & Chih-Yang Huang

  2. Athletic Training and Health Department, National Taiwan Sport University, Taoyuan, 333, Taiwan

    Ying-Lan Tsai

  3. Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, ROC

    Marthandam Asokan Shibu, Chia-chi Su & Chih-Yang Huang

  4. Department of Hospital and Health Care Administration, Chia Nan University of Pharmacy & Science, Tainan, Taiwan

    Li-Chin Chung

  5. Department of Dermatology, Taipei City Hospital, Taipei, Taiwan

    Peiying Pai

  6. Chinese Medicine Department, China Medical University Beigang Hospital, Yunlin, Taiwan

    Chia-Hua Kuo

  7. Department of pathology, Changhua Christian Hospital, Changhua, Taiwan

    Yu-Lan Yeh

  8. Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan

    Yu-Lan Yeh

  9. Department of Biotechnology, Bharathiar University, Coimbatore, 641 046, India

    Vijaya Padma Viswanadha

  10. Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan

    Chih-Yang Huang

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  1. You-Liang Hsieh
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Correspondence to Chih-Yang Huang.

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Hsieh, YL., Tsai, YL., Shibu, M.A. et al. ZAK induces cardiomyocyte hypertrophy and brain natriuretic peptide expression via p38/JNK signaling and GATA4/c-Jun transcriptional factor activation. Mol Cell Biochem 405, 1–9 (2015). https://doi.org/10.1007/s11010-015-2389-z

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  • DOI: https://doi.org/10.1007/s11010-015-2389-z

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