Skip to main content

Advertisement

SpringerLink
Log in

ZAK induces MMP-2 activity via JNK/p38 signals and reduces MMP-9 activity by increasing TIMP-1/2 expression in H9c2 cardiomyoblast cells

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Leucine-zipper and sterile-alpha motif kinase (ZAK) is the key intra-cellular mediator protein in cardiomyocyte hypertrophy induction by transforming growth factor beta 1 (TGF-β1) which has also been identified as a profibrotic cytokine involved in cardiac fibrosis progression. We hypothesized whether ZAK over-expression causes cardiac scar formation due to the extra-cellular matrix (ECM) degraded enzyme regulation in this paper. Using immuno-histochemical analysis of the human cardiovascular tissue array, we found a positively significant association between ZAK over-expression and myocardial scars. ZAK over-expression in H9c2 cardiomyoblast cells increases the metalloproteinase tissue inhibitor 1/2 (TIMP-1/2) protein level, which reduces matria metalloproteinase-9 (MMP-9) activity and also activates c-JNK N-terminal kinase 1/2 (JNK1/2) and p38 signaling, which induces MMP-2, possibly resulting in cardiac fibrosis. Taken together, ZAK activity inhibition may be a good strategy to prevent the cardiac fibrosis progression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

ZAK:

Leucine-zipper and sterile-alpha motif kinase

ECM:

Extra-cellular matrix

PA:

Plasminogen activation

PAI-1:

Plasminogen activator inhibitors

TIMP:

Tissue inhibitors of metalloproteinase

MMP:

Matria metalloproteinase

TGF-β:

Transforming growth factor beta

MLK:

Mixed lineage protein kinase

ANP:

Atrial natriuretic peptide

MAK3K:

Mitogen-activated protein kinase

JNK:

c-JNK N-terminal kinase

ERK:

Extra-cellular signal regulated kinase

MKK7:

MAP kinase kinase 7

SAPKs:

Stress-activated protein kinases

References

  1. Vasan RS, Benjamin EJ (2001) Diastolic heart failure—no time to relax. N Engl J Med 344(1):56–59. doi:10.1056/NEJM200101043440111

    Article  PubMed  CAS  Google Scholar 

  2. Jalil JE, Doering CW, Janicki JS, Pick R, Shroff SG, Weber KT (1989) Fibrillar collagen and myocardial stiffness in the intact hypertrophied rat left ventricle. Circ Res 64(6):1041–1050

    PubMed  CAS  Google Scholar 

  3. Berk BC, Fujiwara K, Lehoux S (2007) ECM remodeling in hypertensive heart disease. J Clin Invest 117(3):568–575. doi:10.1172/JCI31044

    Article  PubMed  CAS  Google Scholar 

  4. Cleutjens JP, Creemers EE (2002) Integration of concepts: cardiac extracellular matrix remodeling after myocardial infarction. J Card Fail 8(6):S344–S348. doi:10.1054/jcaf.2002.129261 (suppl)

    Article  PubMed  CAS  Google Scholar 

  5. Li H, Simon H, Bocan TM, Peterson JT (2000) MMP/TIMP expression in spontaneously hypertensive heart failure rats: the effect of ACE- and MMP-inhibition. Cardiovasc Res 46(2):298–306. doi:10.1016/S0008-6363(00)00028-6

    Article  PubMed  CAS  Google Scholar 

  6. Li YY, McTiernan CF, Feldman AM (2000) Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling. Cardiovasc Res 46(2):214–224. doi:10.1016/S0008-6363(00)00003-1

    Article  PubMed  CAS  Google Scholar 

  7. Gaertner R, Jacob MP, Prunier F, Angles-Cano E, Mercadier JJ, Michel JB (2005) The plasminogen-MMP system is more activated in the scar than in viable myocardium 3 months post-MI in the rat. J Mol Cell Cardiol 38(1):193–204. doi:10.1016/j.yjmcc.2004.10.017

    Article  PubMed  CAS  Google Scholar 

  8. Fay WP (2004) Plasminogen activator inhibitor 1, fibrin, and the vascular response to injury. Trends Cardiovasc Med 14(5):196–202. doi:10.1016/j.tcm.2004.03.002

    Article  PubMed  CAS  Google Scholar 

  9. Spinale FG, Coker ML, Heung LJ, Bond BR, Gunasinghe HR, Etoh T, Goldberg AT, Zellner JL, Crumbley AJ (2000) A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure. Circulation 102(16):1944–1949

    PubMed  CAS  Google Scholar 

  10. Moshal KS, Tyagi N, Moss V, Henderson B, Steed M, Ovechkin A, Aru GM, Tyagi SC (2005) Early induction of matrix metalloproteinase-9 transduces signaling in human heart end stage failure. J Cell Mol Med 9(3):704–713. doi:10.1111/j.1582-4934.2005.tb00501.x

    Article  PubMed  CAS  Google Scholar 

  11. Heymans S, Lupu F, Terclavers S, Vanwetswinkel B, Herbert JM, Baker A, Collen D, Carmeliet P, Moons L (2005) Loss or inhibition of uPA or MMP-9 attenuates LV remodeling and dysfunction after acute pressure overload in mice. Am J Pathol 166(1):15–25

    PubMed  CAS  Google Scholar 

  12. Ducharme A, Frantz S, Aikawa M, Rabkin E, Lindsey M, Rohde LE, Schoen FJ, Kelly RA, Werb Z, Libby P et al (2000) Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J Clin Invest 106(1):55–62. doi:10.1172/JCI8768

    Article  PubMed  CAS  Google Scholar 

  13. Heymans S, Luttun A, Nuyens D, Theilmeier G, Creemers E, Moons L, Dyspersin GD, Cleutjens JP, Shipley M, Angellilo A et al (1999) Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. Nat Med 5(10):1135–1142. doi:10.1038/13459

    Article  PubMed  CAS  Google Scholar 

  14. Peterson JT, Hallak H, Johnson L, Li H, O’Brien PM, Sliskovic DR, Bocan TM, Coker ML, Etoh T, Spinale FG (2001) Matrix metalloproteinase inhibition attenuates left ventricular remodeling and dysfunction in a rat model of progressive heart failure. Circulation 103(18):2303–2309

    PubMed  CAS  Google Scholar 

  15. Leask A, Abraham DJ (2004) TGF-beta signaling and the fibrotic response. FASEB J 18(7):816–827. doi:10.1096/fj.03-1273rev

    Article  PubMed  CAS  Google Scholar 

  16. Okada H, Takemura G, Kosai K, Li Y, Takahashi T, Esaki M, Yuge K, Miyata S, Maruyama R, Mikami A et al (2005) Post-infarction gene therapy against transforming growth factor-beta signal modulates infarct tissue dynamics and attenuates left ventricular remodeling and heart failure. Circulation 111(19):2430–2437. doi:10.1161/01.CIR.0000165066.71481.8E

    Article  PubMed  CAS  Google Scholar 

  17. Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signaling. Nature 425(6958):577–584. doi:10.1038/nature02006

    Article  PubMed  CAS  Google Scholar 

  18. Bujak M, Frangogiannis NG (2007) The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res 74(2):184–195. doi:10.1016/j.cardiores.2006.10.002

    Article  PubMed  CAS  Google Scholar 

  19. 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(3):811–816. doi:10.1006/bbrc.2000.3236

    Article  PubMed  CAS  Google Scholar 

  20. Gallo KA, Johnson GL (2002) Mixed-lineage kinase control of JNK and p38 MAPK pathways. Nat Rev Mol Cell Biol 3(9):663–672. doi:10.1038/nrm906

    Article  PubMed  CAS  Google Scholar 

  21. Huang CY, Chueh PJ, Tseng CT, Liu KY, Tsai HY, Kuo WW, Chou MY, Yang JJ (2004) ZAK re-programs a trial natriuretic factor expression and induces hypertrophic growth in H9c2 cardiomyoblast cells. Biochem Biophys Res Commun 324(3):973–980

    Article  PubMed  CAS  Google Scholar 

  22. Huang CY, Kuo WW, Chueh PJ, Tseng CT, Chou MY, Yang JJ (2004) Transforming growth factor-beta induces the expression of ANP and hypertrophic growth in cultured cardiomyoblast cells through ZAK. Biochem Biophys Res Commun 324(1):424–431. doi:10.1016/j.bbrc.2004.09.067

    Article  PubMed  CAS  Google Scholar 

  23. 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 Biophys Res Commun 297(1):105–110. doi:10.1016/S0006-291X(02)02123-X

    Article  PubMed  CAS  Google Scholar 

  24. Vanhoutte D, Schellings M, Pinto Y, Heymans S (2006) Relevance of matrix metalloproteinases and their inhibitors after myocardial infarction: a temporal and spatial window. Cardiovasc Res 69(3):604–613. doi:10.1016/j.cardiores.2005.10.002

    Article  PubMed  CAS  Google Scholar 

  25. Deschamps AM, Spinale FG (2006) Pathways of matrix metalloproteinase induction in heart failure: bioactive molecules and transcriptional regulation. Cardiovasc Res 69(3):666–676. doi:10.1016/j.cardiores.2005.10.004

    Article  PubMed  CAS  Google Scholar 

  26. Orn S, Manhenke C, Squire IB, Ng L, Anand I, Dickstein K (2007) Plasma MMP-2, MMP-9 and N-BNP in long-term survivors following complicated myocardial infarction: relation to cardiac magnetic resonance imaging measures of left ventricular structure and function. J Card Fail 13(10):843–849. doi:10.1016/j.cardfail.2007.07.006

    Article  PubMed  CAS  Google Scholar 

  27. Mukherjee R, Mingoia JT, Bruce JA, Austin JS, Stroud RE, Escobar GP, McClister DM Jr, Allen CM, Alfonso-Jaume MA, Fini ME, Lovett DH, Spinale FG (2006) Selective spatiotemporal induction of matrix metalloproteinase-2 and matrix metalloproteinase-9 transcription after myocardial infarction. Am J Physiol Heart Circ Physiol 291(5):H2216–H2228. doi:10.1152/ajpheart.01343.2005

    Article  PubMed  CAS  Google Scholar 

  28. Wu DJ, Lin JA, Chiu YT, Cheng CC, Shyu CL, Ueng KC, Huang CY (2003) Pathological and biochemical analysis of dilated cardiomyopathy of broiler chickens—an animal model. Chin J Physiol 46(1):19–26

    PubMed  Google Scholar 

  29. Schiller M, Javelaud D, Mauviel A (2004) TGF-beta-induced SMAD signaling and gene regulation: consequences for extracellular matrix remodeling and wound healing. J Dermatol Sci 35(2):83–92. doi:10.1016/j.jdermsci.2003.12.006

    Article  PubMed  CAS  Google Scholar 

  30. Verrecchia F, Chu ML, Mauviel A (2001) Identification of novel TGF-beta/Smad gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach. J Biol Chem 276(20):17058–17062. doi:10.1074/jbc.M100754200

    Article  PubMed  CAS  Google Scholar 

  31. Stawowy P, Margeta C, Kallisch H, Seidah NG, Chretien M, Fleck E, Graf K (2004) Regulation of matrix metalloproteinase MT1-MMP/MMP-2 in cardiac fibroblasts by TGF-beta1 involves furin-convertase. Cardiovasc Res 63(1):87–97. doi:10.1016/j.cardiores.2004.03.010

    Article  PubMed  CAS  Google Scholar 

  32. Baines CP, Molkentin JD (2005) STRESS signaling pathways that modulate cardiac myocyte apoptosis. J Mol Cell Cardiol 38(1):47–62. doi:10.1016/j.yjmcc.2004.11.004

    Article  PubMed  CAS  Google Scholar 

  33. Liang Q, Molkentin JD (2003) Redefining the roles of p38 and JNK signaling in cardiac hypertrophy: dichotomy between cultured myocytes and animal models. J Mol Cell Cardiol 35(12):1385–1394. doi:10.1016/j.yjmcc.2003.10.001

    Article  PubMed  CAS  Google Scholar 

  34. Aoki H, Kang PM, Hampe J, Yoshimura K, Noma T, Matsuzaki M, Izumo S (2002) Direct activation of mitochondrial apoptosis machinery by c-Jun N-terminal kinase in adult cardiac myocytes. J Biol Chem 277(12):10244–10250. doi:10.1074/jbc.M112355200

    Article  PubMed  CAS  Google Scholar 

  35. Kang YJ, Zhou ZX, Wang GW, Buridi A, Klein JB (2000) Suppression by metallothionein of doxorubicin-induced cardiomyocyte apoptosis through inhibition of p38 mitogen-activated protein kinases. J Biol Chem 275(18):13690–13698. doi:10.1074/jbc.275.18.13690

    Article  PubMed  CAS  Google Scholar 

  36. Mackay K, Mochly-Rosen D (1999) An inhibitor of p38 mitogen-activated protein kinase protects neonatal cardiac myocytes from ischemia. J Biol Chem 274(10):6272–6279. doi:10.1074/jbc.274.10.6272

    Article  PubMed  CAS  Google Scholar 

  37. Mackay K, Mochly-Rosen D (2000) Involvement of a p38 mitogen-activated protein kinase phosphatase in protecting neonatal rat cardiac myocytes from ischemia. J Mol Cell Cardiol 32(8):1585–1588. doi:10.1006/jmcc.2000.1194

    Article  PubMed  CAS  Google Scholar 

  38. Weber KT (1997) Monitoring tissue repair and fibrosis from a distance. Circulation 96(8):2488–2492

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Emergency Department, China Medical University Hospital, Taichung, Taiwan

    Yi-Chang Cheng

  2. Department of Biological Science and Technology, China Medical University, Taichung, 404, Taiwan

    Wei-Wen Kuo & Chun-Hsien Wu

  3. School of Medicine, China Medical University Hospital, Taichung, Taiwan

    Hsi-Chin Wu

  4. Post-Baccalaureate School of Chinese Medicine, China Medical University, Taichung, 404, Taiwan

    Tung-Yuan Lai

  5. School of Applied Chemistry, Chung-Shan Medical University, Taichung, Taiwan

    Jin-Ming Hwang

  6. Department of Nutrition, Taichung Veterans General Hospital, Taichung, Taiwan

    Wen-Hong Wang

  7. Department of Pediatrics, Medical Research and Medical Genetics, China Medical University, Taichung, Taiwan

    Fuu-Jen Tsai

  8. School of Dentistry, Chung-Shan Medical University, Taichung, Taiwan

    Jaw-Ji Yang

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

    Chih-Yang Huang

  10. Graduate Institute of Basic Medical Science, China Medical University, No. 91, Hsueh-Shih Road, Taichung, 404, Taiwan

    Chih-Yang Huang & Chun-Hsien Chu

  11. Department of Health and Nutrition Biotechnology, Asia University, Taichung, 413, Taiwan

    Chih-Yang Huang

Authors
  1. Yi-Chang Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wei-Wen Kuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hsi-Chin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tung-Yuan Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chun-Hsien Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jin-Ming Hwang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wen-Hong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fuu-Jen Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jaw-Ji Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chih-Yang Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Chun-Hsien Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chun-Hsien Chu.

Additional information

Jaw-Ji Yang, Chih-Yang Huang, and Chun-Hsien Chu contributed equally to this paper.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cheng, YC., Kuo, WW., Wu, HC. et al. 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 (2009). https://doi.org/10.1007/s11010-008-0021-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-008-0021-1

Keywords

Search

Navigation