Skip to main content

Advertisement

SpringerLink
Log in

Vinexin-β protects against cardiac hypertrophy by blocking the Akt-dependent signalling pathway

  • Original Contribution
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Cardiac hypertrophy is the heart’s response to hypertrophic stimuli and is associated with increased mortality. Vinexin-β is a vinculin-binding protein that belongs to a family of adaptor proteins and mediates signal transduction and actin cytoskeleton organisation. A previous study has shown that Vinexin-β is ubiquitously expressed and that it is highly expressed in the heart. However, a critical role for Vinexin-β in cardiac hypertrophy has not been investigated. Therefore, to examine the role of Vinexin-β in pathological cardiac hypertrophy, we used Vinexin-β knockout mice and transgenic mice that overexpress human Vinexin-β in the heart. Cardiac hypertrophy was induced by aortic banding (AB). The extent of cardiac hypertrophy was quantitated by echocardiography and pathological and molecular analyses of heart samples. Our results demonstrated that Vinexin-β overexpression in the heart markedly attenuated cardiac hypertrophy, fibrosis, and cardiac dysfunction, whereas loss of Vinexin-β exaggerated the pathological cardiac remodelling and fibrosis response to pressure overload. Further analysis of the in vitro and in vivo signalling events indicated that beneficial Vinexin-β effects were associated with AKT signalling abrogation. Our findings demonstrate for the first time that Vinexin-β is a novel mediator that protects against cardiac hypertrophy by blocking the AKT signalling pathway.

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
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Akamatsu M, Aota S, Suwa A, Ueda K, Amachi T, Yamada KM, Akiyama SK, Kioka N (1999) Vinexin forms a signaling complex with Sos and modulates epidermal growth factor-induced c-Jun N-terminal kinase/stress-activated protein kinase activities. J Biol Chem 274:35933–35937. doi:10.1074/jbc.274.50.35933

    Article  PubMed  CAS  Google Scholar 

  2. Bian Z, Cai J, Shen DF, Chen L, Yan L, Tang Q, Li H (2009) Cellular repressor of E1A-stimulated genes attenuates cardiac hypertrophy and fibrosis. J Cell Mol Med 13:1302–1313. doi:10.1111/j.1582-4934.2008.00633.x

    Article  PubMed  CAS  Google Scholar 

  3. Braz JC, Bueno OF, Liang Q, Wilkins BJ, Dai YS, Parsons S, Braunwart J, Glascock BJ, Klevitsky R, Kimball TF, Hewett TE, Molkentin JD (2003) Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling. J Clin Invest 111:1475–1486. doi:10.1172/jci200317295

    PubMed  CAS  Google Scholar 

  4. Carneiro-Ramos MS, Diniz GP, Nadu AP, Almeida J, Vieira RL, Santos RA, Barreto-Chaves ML (2010) Blockage of angiotensin II type 2 receptor prevents thyroxine-mediated cardiac hypertrophy by blocking Akt activation. Basic Res Cardiol 105:325–335. doi:10.1007/s00395-010-0089-0

    Article  PubMed  CAS  Google Scholar 

  5. Condorelli G, Drusco A, Stassi G, Bellacosa A, Roncarati R, Iaccarino G, Russo MA, Gu Y, Dalton N, Chung C, Latronico MV, Napoli C, Sadoshima J, Croce CM, Ross J Jr (2002) Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice. Proc Natl Acad Sci USA 99:12333–12338. doi:10.1073/pnas.172376399

    Article  PubMed  CAS  Google Scholar 

  6. DeBosch B, Treskov I, Lupu TS, Weinheimer C, Kovacs A, Courtois M, Muslin AJ (2006) Akt1 is required for physiological cardiac growth. Circulation 113:2097–2104. doi:10.1161/CIRCULATIONAHA.105.595231

    Article  PubMed  CAS  Google Scholar 

  7. Diniz GP, Carneiro-Ramos MS, Barreto-Chaves ML (2009) Angiotensin type 1 receptor mediates thyroid hormone-induced cardiomyocyte hypertrophy through the Akt/GSK-3beta/mTOR signaling pathway. Basic Res Cardiol 104:653–667. doi:10.1007/s00395-009-0043-1

    Article  PubMed  CAS  Google Scholar 

  8. Dorn GW 2nd, Force T (2005) Protein kinase cascades in the regulation of cardiac hypertrophy. J Clin Invest 115:527–537. doi:10.1172/JCI24178

    PubMed  CAS  Google Scholar 

  9. Esposito G, Perrino C, Cannavo A, Schiattarella GG, Borgia F, Sannino A, Pironti G, Gargiulo G, di Serafino L, Franzone A, Scudiero L, Grieco P, Indolfi C, Chiariello M (2011) EGFR trans-activation by urotensin II receptor is mediated by beta-arrestin recruitment and confers cardioprotection in pressure overload-induced cardiac hypertrophy. Basic Res Cardiol 106:577–589. doi:10.1007/s00395-011-0163-2

    Article  PubMed  CAS  Google Scholar 

  10. Garlie JB, Hamid T, Gu Y, Ismahil MA, Chandrasekar B, Prabhu SD (2011) Tumor necrosis factor receptor 2 signaling limits beta-adrenergic receptor-mediated cardiac hypertrophy in vivo. Basic Res Cardiol 106:1193–1205. doi:10.1007/s00395-011-0196-6

    Article  PubMed  CAS  Google Scholar 

  11. Hardt SE, Sadoshima J (2002) Glycogen synthase kinase-3beta: a novel regulator of cardiac hypertrophy and development. Circ Res 90:1055–1063. doi:10.1161/01.RES.0000018952.70505.F1

    Article  PubMed  CAS  Google Scholar 

  12. 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  PubMed  CAS  Google Scholar 

  13. Heusch G (2009) Diastolic heart failure: a misNOmer. Basic Res Cardiol 104:465–467. doi:10.1007/s00395-009-0025-3

    Article  PubMed  Google Scholar 

  14. Heusch G (2011) SCIPIO brings new momentum to cardiac cell therapy. Lancet 378:1827–1828. doi:10.1016/S0140-6736(11)61648-6

    Article  PubMed  Google Scholar 

  15. Heusch G, Kleinbongard P, Skyschally A, Levkau B, Schulz R, Erbel R (2012) The coronary circulation in cardioprotection: more than just one confounder. Cardiovasc Res 94:237–245. doi:10.1093/cvr/cvr271

    Article  PubMed  CAS  Google Scholar 

  16. Heusch G, Neumann T (1998) Calcium responsiveness in canine pacing-induced heart failure. J Mol Cell Cardiol 30:1605–1613. doi:10.1006/jmcc.1998.0726

    Article  PubMed  CAS  Google Scholar 

  17. Heusch G, Schulz R (2011) A radical view on the contractile machinery in human heart failure. J Am Coll Cardiol 57:310–312. doi:10.1016/j.jacc.2010.06.057

    Article  PubMed  CAS  Google Scholar 

  18. Heusch P, Canton M, Aker S, van de Sand A, Konietzka I, Rassaf T, Menazza S, Brodde OE, Di Lisa F, Heusch G, Schulz R (2010) The contribution of reactive oxygen species and p38 mitogen-activated protein kinase to myofilament oxidation and progression of heart failure in rabbits. Br J Pharmacol 160:1408–1416. doi:10.1111/j.1476-5381.2010.00793.x

    Article  PubMed  CAS  Google Scholar 

  19. Hua Y, Zhang Y, Ceylan-Isik AF, Wold LE, Nunn JM, Ren J (2011) Chronic Akt activation accentuates aging-induced cardiac hypertrophy and myocardial contractile dysfunction: role of autophagy. Basic Res Cardiol 106:1173–1191. doi:10.1007/s00395-011-0222-8

    Article  PubMed  CAS  Google Scholar 

  20. Huang H, Tang QZ, Wang AB, Chen M, Yan L, Liu C, Jiang H, Yang Q, Bian ZY, Bai X, Zhu LH, Wang L, Li H (2010) Tumor suppressor A20 protects against cardiac hypertrophy and fibrosis by blocking transforming growth factor-beta-activated kinase 1-dependent signaling. Hypertension 56:232–239. doi:10.1161/HYPERTENSIONAHA.110.149963

    Article  PubMed  CAS  Google Scholar 

  21. Kioka N, Sakata S, Kawauchi T, Amachi T, Akiyama SK, Okazaki K, Yaen C, Yamada KM, Aota S (1999) Vinexin: a novel vinculin-binding protein with multiple SH3 domains enhances actin cytoskeletal organization. J Cell Biol 144:59–69. doi:10.1083/jcb.144.1.59

    Article  PubMed  CAS  Google Scholar 

  22. Kioka N, Ueda K, Amachi T (2002) Vinexin, CAP/ponsin, ArgBP2: a novel adaptor protein family regulating cytoskeletal organization and signal transduction. Cell Struct Funct 27:1–7

    Article  PubMed  CAS  Google Scholar 

  23. Kovacic-Milivojevic B, Roediger F, Almeida EAC, Damsky CH, Gardner DG, Ilic D (2001) Focal adhesion kinase and p130Cas mediate both sarcomeric organization and activation of genes associated with cardiac myocyte hypertrophy. Mol Biol Cell 12:2290–2307

    PubMed  CAS  Google Scholar 

  24. Krusche CA, Holthofer B, Hofe V, van de Sandt AM, Eshkind L, Bockamp E, Merx MW, Kant S, Windoffer R, Leube RE (2011) Desmoglein 2 mutant mice develop cardiac fibrosis and dilation. Basic Res Cardiol 106:617–633. doi:10.1007/s00395-011-0175-y

    Article  PubMed  CAS  Google Scholar 

  25. Li H, He C, Feng J, Zhang Y, Tang Q, Bian Z, Bai X, Zhou H, Jiang H, Heximer SP, Qin M, Huang H, Liu PP, Huang C (2010) Regulator of G protein signaling 5 protects against cardiac hypertrophy and fibrosis during biomechanical stress of pressure overload. Proc Natl Acad Sci USA 107:13818–13823. doi:10.1073/pnas.1008397107

    Article  PubMed  CAS  Google Scholar 

  26. Li HL, Zhuo ML, Wang D, Wang AB, Cai H, Sun LH, Yang Q, Huang Y, Wei YS, Liu PP, Liu DP, Liang CC (2007) Targeted cardiac overexpression of A20 improves left ventricular performance and reduces compensatory hypertrophy after myocardial infarction. Circulation 115:1885–1894. doi:10.1161/CIRCULATIONAHA.106.656835

    Article  PubMed  CAS  Google Scholar 

  27. Lorell BH, Carabello BA (2000) Left ventricular hypertrophy: pathogenesis, detection, and prognosis. Circulation 102:470–479. doi:10.1161/01.CIR.102.4.470

    Article  PubMed  CAS  Google Scholar 

  28. Lu J, Bian ZY, Zhang R, Zhang Y, Liu C, Yan L, Zhang SM, Jiang DS, Wei X, Zhu XH, Chen M, Wang AB, Chen Y, Yang Q, Liu PP, Li H (2013) Interferon regulatory factor 3 is a negative regulator of pathological cardiac hypertrophy. Basic Res Cardiol 108:326. doi:10.1007/s00395-012-0326-9

    Article  PubMed  Google Scholar 

  29. Matsui T, Li L, Wu JC, Cook SA, Nagoshi T, Picard MH, Liao R, Rosenzweig A (2002) Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart. J Biol Chem 277:22896–22901. doi:10.1074/jbc.M200347200

    Article  PubMed  CAS  Google Scholar 

  30. Matsuyama M, Mizusaki H, Shimono A, Mukai T, Okumura K, Abe K, Shimada K, Morohashi K (2005) A novel isoform of Vinexin, Vinexin gamma, regulates Sox9 gene expression through activation of MAPK cascade in mouse fetal gonad. Genes Cells 10:421–434. doi:10.1111/j.1365-2443.2005.00844.x

    Article  PubMed  CAS  Google Scholar 

  31. Miller CL, Cai Y, Oikawa M, Thomas T, Dostmann WR, Zaccolo M, Fujiwara K, Yan C (2011) Cyclic nucleotide phosphodiesterase 1A: a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart. Basic Res Cardiol 106:1023–1039. doi:10.1007/s00395-011-0228-2

    Article  PubMed  CAS  Google Scholar 

  32. Miyamoto T, Takeishi Y, Takahashi H, Shishido T, Arimoto T, Tomoike H, Kubota I (2004) Activation of distinct signal transduction pathways in hypertrophied hearts by pressure and volume overload. Basic Res Cardiol 99:328–337. doi:10.1007/s00395-004-0482-7

    Article  PubMed  CAS  Google Scholar 

  33. Molkentin JD (2004) Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs. Cardiovasc Res 63:467–475. doi:10.1016/j.cardiores.2004.01.021

    Article  PubMed  CAS  Google Scholar 

  34. Ruilope LM, Schmieder RE (2008) Left ventricular hypertrophy and clinical outcomes in hypertensive patients. Am J Hypertens 21:500–508. doi:10.1038/ajh.2008.16

    Article  PubMed  Google Scholar 

  35. Shioi T, McMullen JR, Kang PM, Douglas PS, Obata T, Franke TF, Cantley LC, Izumo S (2002) Akt/protein kinase B promotes organ growth in transgenic mice. Mol Cell Biol 22:2799–2809. doi:10.1128/MCB.22.8.2799-2809.2002

    Article  PubMed  CAS  Google Scholar 

  36. Shiojima I, Sato K, Izumiya Y, Schiekofer S, Ito M, Liao R, Colucci WS, Walsh K (2005) Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest 115:2108–2118. doi:10.1172/JCI24682

    Article  PubMed  CAS  Google Scholar 

  37. Suwa A, Mitsushima M, Ito T, Akamatsu M, Ueda K, Amachi T, Kioka N (2002) Vinexin beta regulates the anchorage dependence of ERK2 activation stimulated by epidermal growth factor. J Biol Chem 277:13053–13058. doi:10.1074/jbc.M108644200

    Article  PubMed  CAS  Google Scholar 

  38. Umemoto T, Inomoto T, Ueda K, Hamaguchi M, Kioka N (2009) v-Src-mediated transformation suppresses the expression of focal adhesion protein vinexin. Cancer Lett 279:22–29. doi:10.1016/j.canlet.2009.01.017

    Article  PubMed  CAS  Google Scholar 

  39. Wenzel S, Henning K, Habbig A, Forst S, Schreckenberg R, Heger J, Maxeiner H, Schluter KD (2010) TGF-beta1 improves cardiac performance via up-regulation of laminin receptor 37/67 in adult ventricular cardiomyocytes. Basic Res Cardiol 105:621–629. doi:10.1007/s00395-010-0108-1

    Article  PubMed  CAS  Google Scholar 

  40. Xiao J, Moon M, Yan L, Nian M, Zhang Y, Liu C, Lu J, Guan H, Chen M, Jiang D, Jiang H, Liu PP, Li H (2012) Cellular FLICE-inhibitory protein protects against cardiac remodelling after myocardial infarction. Basic Res Cardiol 107:239. doi:10.1007/s00395-011-0239-z

    Article  PubMed  Google Scholar 

  41. Xu Z, Desai M, Philip J, Sivsubramanian N, Bowles NE, Vallejo JG (2011) Conditional transgenic expression of TIR-domain-containing adaptor-inducing interferon-beta (TRIF) in the adult mouse heart is protective in acute viral myocarditis. Basic Res Cardiol 106:1159–1171. doi:10.1007/s00395-011-0226-4

    Article  PubMed  CAS  Google Scholar 

  42. Yan L, Wei X, Tang QZ, Feng J, Zhang Y, Liu C, Bian ZY, Zhang LF, Chen M, Bai X, Wang AB, Fassett J, Chen Y, He YW, Yang Q, Liu PP, Li H (2011) Cardiac-specific mindin overexpression attenuates cardiac hypertrophy via blocking AKT/GSK3beta and TGF-beta1-Smad signalling. Cardiovasc Res 92:85–94. doi:10.1093/cvr/cvr159

    Article  PubMed  CAS  Google Scholar 

  43. Zhang S, Weinheimer C, Courtois M, Kovacs A, Zhang CE, Cheng AM, Wang Y, Muslin AJ (2003) The role of the Grb2-p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis. J Clin Invest 111:833–841. doi:10.1172/JCI16290

    PubMed  CAS  Google Scholar 

  44. Zhu Y, Li T, Song J, Liu C, Hu Y, Que L, Ha T, Kelley J, Chen Q, Li C, Li Y (2011) The TIR/BB-loop mimetic AS-1 prevents cardiac hypertrophy by inhibiting IL-1R-mediated MyD88-dependent signaling. Basic Res Cardiol 106:787–799. doi:10.1007/s00395-011-0182-z

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The Vinexin-β knockout mouse model was provided by the RIKEN BRC through the National BioResource Project of the MEXT, Japan. This study was supported by the National Natural Science Foundation of China (Grant Nos. 81170086, 81200071, 3087451 and 30801351), National Science and Technology Support Project (No. 2011BAI15B02 and No. 2012BAI39B05), and the National Basic Research Program of China (Grant No. 2011CB503902) and the Fundamental Research Funds for the Central Universities of China (302274021).

Conflict of interest

The authors declare that no conflict of interest exists.

Author information

Authors and Affiliations

  1. College of Life Sciences, Wuhan University, Wuhan, 430072, People’s Republic of China

    Ke Chen & Xiao-Dong Zhang

  2. Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China

    Lu Gao

  3. Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, People’s Republic of China

    Yu Liu, Yan Zhang, Ding-Sheng Jiang & Hongliang Li

  4. Cardiovascular Research Institute of Wuhan University, Jiefang Road 238, Wuhan, 430060, People’s Republic of China

    Yan Zhang, Ding-Sheng Jiang, Rui Zhang & Hongliang Li

  5. Department of Thoracic and Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China

    Xiang Wei & Xue Hai Zhu

  6. Cardiovascular Division, University of Minnesota, Minneapolis, MN, 55455, USA

    Yingjie Chen

  7. Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, 35294-3360, USA

    Qinglin Yang

  8. Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Sakyo, Kyoto, Japan

    Noriyuki Kioka

Authors
  1. Ke Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lu Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ding-Sheng Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiang Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xue Hai Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yingjie Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Qinglin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Noriyuki Kioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xiao-Dong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hongliang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Xiao-Dong Zhang or Hongliang Li.

Additional information

K. Chen, L. Gao and Y. Liu are co-first authors.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 15 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, K., Gao, L., Liu, Y. et al. Vinexin-β protects against cardiac hypertrophy by blocking the Akt-dependent signalling pathway. Basic Res Cardiol 108, 338 (2013). https://doi.org/10.1007/s00395-013-0338-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00395-013-0338-0

Keywords

Search

Navigation