SpringerLink
Log in

Gelsolin (GSN) induces cardiomyocyte hypertrophy and BNP expression via p38 signaling and GATA-4 transcriptional factor activation

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

Abstract

Cardiomyocyte hypertrophy is an adaptive response of the heart to various types of stress. During the period of stress accumulation, the transition from physiological hypertrophy to pathological hypertrophy results in the promotion of heart failure. Gelsolin (GSN) is a member of the actin-binding proteins, which regulate dynamic actin filament organization by severing and cap**. Moreover, GSN also regulates cell morphology, differentiation, movement, and apoptosis. In this study, we used H9c2 and H9c2-GSN stable clones in an attempt to understand the mechanisms of GSN overexpression in cardiomyocytes. These data showed that the overexpression of GSN in H9c2-induced cardiac hypertrophy and increased the pathological hypertrophy markers atrial natriuretic peptide brain natriuretic peptide. Furthermore, we found that E-cadherin expression decreased with the overexpression of GSN in H9c2, but β-catenin expression increased. These data presume that the cytoskeleton is loose. Further, previous studies show that the mitogen-activated protein kinase pathway can induce cardiac hypertrophy. Our data showed that p-p38 expression increased with the overexpression of GSN in H9c2, and the transcription factor p-GATA4 expression also increased, suggesting that the overexpression of GSN in H9c2-induced cardiac hypertrophy seemed to be regulated by the p38/GATA4 pathway. Moreover, we used both the p38 inhibitor (SB203580) and GSN siRNA to confirm our conjecture. We found that both of these factors significantly suppressed gelsolin-induced cardiac hypertrophy through p38/GATA4 signaling pathway. Therefore, we predict that the gene silencing of GSN and/or the downstream blocking of GSN along the p38 pathway could be applied to ameliorate pathological cardiac hypertrophy in the future.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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
Fig. 5

Similar content being viewed by others

References

  1. Cartwright EJ, Oceandy D, Austin C, Neyses L (2011) Ca2+ signalling in cardiovascular disease: the role of the plasma membrane calcium pumps. Sci China Life Sci 54(8):691–698

    Article  PubMed  CAS  Google Scholar 

  2. Heineke J, Molkentin JD (2006) Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol 7(8):589–600

    Article  PubMed  CAS  Google Scholar 

  3. Lorell BH, Carabello BA (2000) Left ventricular hypertrophy: pathogenesis, detection, and prognosis. Circulation 102(4):470–479

    Article  PubMed  CAS  Google Scholar 

  4. Yamamoto S, Kita S, Iyoda T, Yamada T, Iwamoto T (2011) New molecular mechanisms for cardiovascular disease: cardiac hypertrophy and cell-volume regulation. J Pharmacol Sci 116(4):343–349

    Article  PubMed  CAS  Google Scholar 

  5. Tezuka F, Takahashi T (1976) Pathology of cardiac hypertrophy in pressure overload. Jpn Circ J 40(10):1111–1118

    Article  PubMed  CAS  Google Scholar 

  6. Johnson GL, Lapadat R (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298(5600):1911–1912

    Article  PubMed  CAS  Google Scholar 

  7. Sugden PH, Clerk A (1998) “Stress-responsive” mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogen-activated protein kinases) in the myocardium. Circ Res 83(4):345–352

    Article  PubMed  CAS  Google Scholar 

  8. 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(1 Pt 2):188–192

    Article  PubMed  CAS  Google Scholar 

  9. Garrington TP, Johnson GL (1999) Organization and regulation of mitogen-activated protein kinase signaling pathways. Curr Opin Cell Biol 11(2):211–218

    Article  PubMed  CAS  Google Scholar 

  10. 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(23):24852–24860

    Article  PubMed  CAS  Google Scholar 

  11. 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(16):13752–13760

    Article  PubMed  CAS  Google Scholar 

  12. Silacci P, Mazzolai L, Gauci C, Stergiopulos N, Yin HL, Hayoz D (2004) Gelsolin superfamily proteins: key regulators of cellular functions. Cell Mol Life Sci 61(19–20):2614–2623

    Article  PubMed  CAS  Google Scholar 

  13. Sun HQ, Yamamoto M, Mejillano M, Yin HL (1999) Gelsolin, a multifunctional actin regulatory protein. J Biol Chem 274(47):33179–33182

    Article  PubMed  CAS  Google Scholar 

  14. Li GH, Shi Y, Chen Y, Sun M, Sader S, Maekawa Y, Arab S, Dawood F, Chen M, De Couto G et al (2009) Gelsolin regulates cardiac remodeling after myocardial infarction through DNase I-mediated apoptosis. Circ Res 104(7):896–904

    Article  PubMed  CAS  Google Scholar 

  15. Yin HL, Stossel TP (1979) Control of cytoplasmic actin gel–sol transformation by gelsolin, a calcium-dependent regulatory protein. Nature 281(5732):583–586

    Article  PubMed  CAS  Google Scholar 

  16. McGough AM, Staiger CJ, Min JK, Simonetti KD (2003) The gelsolin family of actin regulatory proteins: modular structures, versatile functions. FEBS Lett 552(2–3):75–81

    Article  PubMed  CAS  Google Scholar 

  17. Kwiatkowski DJ (1999) Functions of gelsolin: motility, signaling, apoptosis, cancer. Curr Opin Cell Biol 11(1):103–108

    Article  PubMed  CAS  Google Scholar 

  18. Li GH, Arora PD, Chen Y, McCulloch CA, Liu P (2012) Multifunctional roles of gelsolin in health and diseases. Med Res Rev 32(5):999–1025

    Article  PubMed  CAS  Google Scholar 

  19. Yang J, Moravec CS, Sussman MA, DiPaola NR, Fu D, Hawthorn L, Mitchell CA, Young JB, Francis GS, McCarthy PM et al (2000) Decreased SLIM1 expression and increased gelsolin expression in failing human hearts measured by high-density oligonucleotide arrays. Circulation 102(25):3046–3052

    Article  PubMed  CAS  Google Scholar 

  20. Mani SK, Shiraishi H, Balasubramanian S, Yamane K, Chellaiah M, Cooper G, Banik N, Zile, Kuppuswamy D (2008) In vivo administration of calpeptin attenuates calpain activation and cardiomyocyte loss in pressure-overloaded feline myocardium. Am J Physiol Heart Circ Physiol 295(1):H314–H326

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  21. Suhler E, Lin W, Yin HL, Lee WM (1997) Decreased plasma gelsolin concentrations in acute liver failure, myocardial infarction, septic shock, and myonecrosis. Crit Care Med 25(4):594–598

    Article  PubMed  CAS  Google Scholar 

  22. Towbin JA, Bowles NE (2002) The failing heart. Nature 415(6868):227–233

    Article  PubMed  CAS  Google Scholar 

  23. Hunter JJ, Chien KR (1999) Signaling pathways for cardiac hypertrophy and failure. N Engl J Med 341(17):1276–1283

    Article  PubMed  CAS  Google Scholar 

  24. Nishio R, Matsumori A (2009) Gelsolin and cardiac myocyte apoptosis: a new target in the treatment of postinfarction remodeling. Circ Res 104(7):829–831

    Article  PubMed  CAS  Google Scholar 

  25. 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(2):215–228

    Article  PubMed  CAS  Google Scholar 

  26. Huang CY, Lee SD (2012) Possible pathophysiology of heart failure in obesity: cardiac apoptosis. BioMedicine 2(1):36–40

  27. Roux PP, Blenis J (2004) ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev 68(2):320–344

    Google Scholar 

  28. Wright CD, Chen Q, Baye NL, Huang Y, Healy CL, Kasinathan S, O’Connell TD (2008) Nuclear alpha1-adrenergic receptors signal activated ERK localization to caveolae in adult cardiac myocytes. Circ Res 103(9):992–1000

    Google Scholar 

Download references

Acknowledgments

This study was supported by grants from Taipei Medical University -Shuang Ho Hospital (102 TMU-SHH-16), CMU 102-S-13 and CMUBH R102-008, also in part by the Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH102-TD-B-111-004).

Author information

Authors and Affiliations

  1. PhD Program for Aging, China Medical University, Taichung, Taiwan, ROC

    Wei-Syun Hu

  2. Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan, ROC

    Wei-Syun Hu

  3. School of Chinese Medicine, China Medical University, Taichung, Taiwan, ROC

    Tsung-Jung Ho, Fuu-Jen Tsai & Chih-Yang Huang

  4. Chinese Medicine Department, China Medical University, Beigang Hospital, Beigang, Taiwan, ROC

    Tsung-Jung Ho

  5. Division of Cardiology, China Medical University Hospital, Taichung, Taiwan, ROC

    Peiying Pai

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

    Li-Chin Chung

  7. Laboratory of Exercise Biochemistry, Taipei Physical Education College, Taipei, Taiwan, ROC

    Chia-Hua Kuo

  8. Department of Health, Tsao-Tun Psychiatric Center, Executive Yuan, Taiwan, ROC

    Sheng-Huang Chang

  9. Department of Healthcare Administration, Asia University, Taichung, Taiwan, ROC

    Chang-Hai Tsai

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

    Yu-Chi Jie & Chih-Yang Huang

  11. Department of Life Sciences, National Chung-Hsing University, Taichung, Taiwan, ROC

    Ying-Ming Liou

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

    Chih-Yang Huang

Authors
  1. Wei-Syun Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tsung-Jung Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peiying Pai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Li-Chin Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chia-Hua Kuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sheng-Huang Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fuu-Jen Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chang-Hai Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yu-Chi Jie
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ying-Ming Liou
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Chih-Yang Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chih-Yang Huang.

Additional information

Y.-M. Liou and C.-Y. Huang share equal contribution.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hu, WS., Ho, TJ., Pai, P. et al. Gelsolin (GSN) induces cardiomyocyte hypertrophy and BNP expression via p38 signaling and GATA-4 transcriptional factor activation. Mol Cell Biochem 390, 263–270 (2014). https://doi.org/10.1007/s11010-014-1977-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-014-1977-7

Keywords

Search

Navigation