Vol 24, No 2 (2017)
Original articles — Basic science and experimental cardiology
Published online: 2016-10-11

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Enhancement of beta-catenin in cardiomyocytes suppresses survival protein expression but promotes apoptosis and fibrosis

James C. Lin, Wei-Wen Kuo, Rathinasamy Baskaran, Ming-Cheng Chen, Tsung-Jung Ho, Ray-Jade Chen, Ya-Fang Chen, Viswanadha Vijaya Padma, Ing-Shiow Lay, Chih-Yang Huang
Pubmed: 27734460
Cardiol J 2017;24(2):195-205.


Background: Beta-catenin has been implicated in cell-cell communication in a wide variety of developmental and physiological processes. Defective Wnt signaling could result in various cardiac and vascular abnormalities. Little is known regarding Wnt/frizzled pathway in cardiomyocyte apoptosis.

Methods: In this study, the role of b-catenin in apoptosis was investigated in H9c2 cardiomyocytes and primary cardiomyocytes isolated in diabetic Wistar rats. The cardiomyocytes were transfected with porcine cytomegalovirus (pCMV)-b-catenin plasmid in order to overexpress b-catenin.

Results: The transcription factor displayed a significant nuclear localization in Wistar rats with cardiac hypertension. Transfection of b-catenin plasmid induced apoptosis and reduced expression of survival pathway markers in cardiomyocytes in a dose-dependent manner. Furthermore, expression of fibrosis protein markers was upregulated by the overexpression. Conclusions: Taken together, these results revealed that altered Wnt/b-catenin signaling might provoke heart failure. (Cardiol J 2017; 24, 2: 195–205)

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  1. Huang CY, Lee SD. Possible pathophysiology of heart failure in obesity: Cardiac apoptosis. BioMedicine. 2012; 2(1): 36–40.
  2. Messaoudi S, Azibani F, Delcayre C, et al. Aldosterone, mineralocorticoid receptor, and heart failure. Mol Cell Endocrinol. 2012; 350(2): 266–272.
  3. Soltysinska E, Olesen SP, Osadchii OE. Myocardial structural, contractile and electrophysiological changes in the guinea-pig heart failure model induced by chronic sympathetic activation. Exp Physiol. 2011; 96(7): 647–663.
  4. Talan MI, Ahmet I, Xiao RP, et al. β₂ AR agonists in treatment of chronic heart failure: long path to translation. J Mol Cell Cardiol. 2011; 51(4): 529–533.
  5. Yin WH, Chen YH, Wei J, et al. Associations between endothelin-1 and adiponectin in chronic heart failure. Cardiology. 2011; 118(4): 207–216.
  6. Distefano G, Sciacca P. Molecular pathogenesis of myocardial remodeling and new potential therapeutic targets in chronic heart failure. Ital J Pediatr. 2012; 38: 41.
  7. Lin WY, Liu HP, Chang JS, et al. Genetic variations within the PSORS1 region affect Kawasaki disease development and coronary artery aneurysm formation. BioMedicine. 2013; 3(2): 73–81.
  8. Palomeque J, Delbridge L, Petroff MV. Angiotensin II: a regulator of cardiomyocyte function and survival. Front Biosci (Landmark Ed). 2009; 14: 5118–5133.
  9. Shah AM, Mann DL. In search of new therapeutic targets and strategies for heart failure: recent advances in basic science. Lancet. 2011; 378(9792): 704–712.
  10. Cooper G. Cardiocyte adaptation to chronically altered load. Annu Rev Physiol. 1987; 49: 501–518.
  11. Mondry A, Swynghedauw B. Biological adaptation of the myocardium to chronic mechanical overload. Molecular determinants of the autonomic nervous system. Eur Heart J. 1995; 16 Suppl I: 64–73.
  12. Ruwhof C, van der Laarse A. Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways. Cardiovasc Res. 2000; 47(1): 23–37.
  13. Diwan A, Dorn GW. Decompensation of cardiac hypertrophy: cellular mechanisms and novel therapeutic targets. Physiology (Bethesda). 2007; 22: 56–64.
  14. van de Schans VAM, Smits JFM, Blankesteijn WM. The Wnt/frizzled pathway in cardiovascular development and disease: friend or foe? Eur J Pharmacol. 2008; 585(2-3): 338–345.
  15. ter Horst P, Smits JFM, Blankesteijn WM. The Wnt/Frizzled pathway as a therapeutic target for cardiac hypertrophy: where do we stand? Acta Physiol (Oxf). 2012; 204(1): 110–117.
  16. Kim K, Pang KM, Evans M, et al. Overexpression of beta-catenin induces apoptosis independent of its transactivation function with LEF-1 or the involvement of major G1 cell cycle regulators. Mol Biol Cell. 2000; 11(10): 3509–3523.
  17. Olmeda D, Castel S, Vilaró S, et al. Beta-catenin regulation during the cell cycle: implications in G2/M and apoptosis. Mol Biol Cell. 2003; 14(7): 2844–2860.
  18. Zhang Z, Deb A, Zhang Z, et al. Secreted frizzled related protein 2 protects cells from apoptosis by blocking the effect of canonical Wnt3a. J Mol Cell Cardiol. 2009; 46(3): 370–377.
  19. Zheng Q, Chen P, Xu Z, et al. Expression and redistribution of β-catenin in the cardiac myocytes of left ventricle of spontaneously hypertensive rat. J Mol Histol. 2013; 44(5): 565–573.
  20. Deb A. Cell-cell interaction in the heart via Wnt/β-catenin pathway after cardiac injury. Cardiovasc Res. 2014; 102(2): 214–223.
  21. Pon YL, Wong AST. Gonadotropin-induced apoptosis in human ovarian surface epithelial cells is associated with cyclooxygenase-2 up-regulation via the beta-catenin/T-cell factor signaling pathway. Mol Endocrinol. 2006; 20(12): 3336–3350.
  22. Jüllig M, Zhang WV, Ferreira A, et al. MG132 induced apoptosis is associated with p53-independent induction of pro-apoptotic Noxa and transcriptional activity of beta-catenin. Apoptosis. 2006; 11(4): 627–641.
  23. Akhmetshina A, Palumbo K, Dees C, et al. Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis. Nat Commun. 2012; 3: 735.
  24. Dawson K, Aflaki M, Nattel S. Role of the Wnt-Frizzled system in cardiac pathophysiology: a rapidly developing, poorly understood area with enormous potential. J Physiol. 2013; 591(6): 1409–1432.
  25. Henderson WR, Chi EY, Ye X, et al. Inhibition of Wnt/beta-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis. Proc Natl Acad Sci U S A. 2010; 107(32): 14309–14314.
  26. He W, Dai C, Li Y, et al. Wnt/beta-catenin signaling promotes renal interstitial fibrosis. J Am Soc Nephrol. 2009; 20(4): 765–776.
  27. Laeremans H, Rensen SS, Ottenheijm HCJ, et al. Wnt/frizzled signalling modulates the migration and differentiation of immortalized cardiac fibroblasts. Cardiovasc Res. 2010; 87(3): 514–523.
  28. Ye Bo, Ge Y, Perens G, et al. Canonical Wnt/β-catenin signaling in epicardial fibrosis of failed pediatric heart allografts with diastolic dysfunction. Cardiovasc Pathol. 2013; 22(1): 54–57.
  29. Guo Z, Xia Z, Yuen VG, et al. Cardiac expression of adiponectin and its receptors in streptozotocin-induced diabetic rats. Metabolism. 2007; 56(10): 1363–1371.
  30. Kanter M, Aksu F, Takir M, et al. Effects of Low Intensity Exercise Against Apoptosis and Oxidative Stress in Streptozotocin-induced Diabetic Rat Heart. Exp Clin Endocrinol Diabetes. 2016 [Epub ahead of print].
  31. Wu KK, Huan YM. Streptozotocin-induced diabetic models in mice and rats. . Curr Protoc Pharmacol. 2008: 5.47.1–5.47.14.
  32. Liu X, Liu C, Li J, et al. Urocortin attenuates myocardial fibrosis in diabetic rats via the Akt/GSK-3β signaling pathway. Endocr Res. 2016; 41(2): 148–157.
  33. Diez J, Fortuno MA, Ravassa S. Apoptosis in hypertensive heart disease. Curr Opin Cardiol. 1998; 130: 317–325.
  34. Fortuño MA, Ravassa S, Fortuño A, et al. Cardiomyocyte apoptotic cell death in arterial hypertension: mechanisms and potential management. Hypertension. 2001; 38(6): 1406–1412.
  35. Flaherty M, Dawn B. Noncanonical Wnt11 signaling and cardiomyogenic differentiation. Trends Cardiovasc Med. 2008; 18(7): 260–268.
  36. Pandey S. Targeting Wnt-Frizzled signaling in cardiovascular diseases. Mol Biol Rep. 2013; 40(10): 6011–6018.
  37. Vanderschuren KLA, Sieverink T, Wilders R. Arrhythmogenic right ventricular dysplasia/cardiomyopathy type 1: a light on molecular mechanisms. Genet Res Int. 2013; 2013: 460805.
  38. Tian YC, Phillips AO. Interaction between the transforming growth factor-beta type II receptor/Smad pathway and beta-catenin during transforming growth factor-beta1-mediated adherens junction disassembly. Am J Pathol. 2002; 160(5): 1619–1628.
  39. Guo Y, Xiao L, Sun L, et al. Wnt/beta-catenin signaling: a promising new target for fibrosis diseases. Physiol Res. 2012; 61(4): 337–346.
  40. Mallat Z, Tedgui A, Fontaliran F, et al. Evidence of apoptosis in arrhythmogenic right ventricular dysplasia. N Engl J Med. 1996; 335(16): 1190–1196.
  41. Yamaji K, Fujimoto S, Ikeda Y, et al. Apoptotic myocardial cell death in the setting of arrhythmogenic right ventricular cardiomyopathy. Acta Cardiol. 2005; 60(5): 465–470.
  42. Hanna C, Hubchak SC, Liang X, et al. Hypoxia-inducible factor-2α and TGF-β signaling interact to promote normoxic glomerular fibrogenesis. Am J Physiol Renal Physiol. 2013; 305(9): F1323–F1331.
  43. Hung SP, Yang MH, Tseng KF, et al. Hypoxia-induced secretion of TGF-β1 in mesenchymal stem cell promotes breast cancer cell progression. Cell Transplant. 2013; 22(10): 1869–1882.
  44. Suzuki YJ. Cell signaling pathways for the regulation of GATA4 transcription factor: Implications for cell growth and apoptosis. Cell Signal. 2011; 23(7): 1094–1099.
  45. Jian H, Shen X, Liu I, et al. Smad3-dependent nuclear translocation of beta-catenin is required for TGF-beta1-induced proliferation of bone marrow-derived adult human mesenchymal stem cells. Genes Dev. 2006; 20(6): 666–674.
  46. Zhou B, Liu Y, Kahn M, et al. Interactions between β-catenin and transforming growth factor-β signaling pathways mediate epithelial-mesenchymal transition and are dependent on the transcriptional co-activator cAMP-response element-binding protein (CREB)-binding protein (CBP). J Biol Chem. 2012; 287(10): 7026–7038.
  47. Zhou S. TGF-β regulates β-catenin signaling and osteoblast differentiation in human mesenchymal stem cells. J Cell Biochem. 2011; 112(6): 1651–1660.