α-Е-CATENIN REGULATES HYPERTROPHIC SIGNALINGS IN HEART

  • V. V. Balatskyy Institute of Molecular Biology and Genetics of NAS of Ukraine
  • L. L. Macewicz Institute of Molecular Biology and Genetics of NAS of Ukraine
  • O. O. Piven Institute of Molecular Biology and Genetics of NAS of Ukraine
Keywords: α-E-catenin, hypertrophy, myocardium, MAPK1/3, PK-В, PK-А

Abstract

Heart disease is the leading cause of death worldwide with the number of people diagnosed ever increasing due to an ageing population also has a great social and economic impact. Recently, the investigation of new method of diagnosis and treatment of cardiovascular diseases are become topical, but also the elucidation of the heart diseases mechanisms are in focus. Taking it to account, the investigation of signaling pathways controlling the normal function of the heart and its adaptation to stress is at the edge of modern cardiac biology.

 

Alpha-Е-catenin is important component of adherent junction in adult myocardium. The structure and function of α-catenin have been studied using experimental mouse models and isolated cells. The early embryonic loss of this gene was shown to disrupt the trophoblast epithelium and block embryonic development in the blastocyst stage. We previously reported that heart-specific knockout of αE-catenin did not affect cardiogenesis or overall embryonic development. We did not observe an increase in lethality in newborn mice. This appeared to be related to functional redundancy between proteins of the adhesion complex, particularly between αE- and αT-catenin. Other studies showed that the ablation of αE-catenin in the adult heart leads to cardiomyopathy and intercalated disc abnormalities. Moreover, in humans, αE-catenin downregulation was observed in areas of myocardial infarction with heart wall rupture, but the precise mechanisms of this downregulation are still unknown.

Recently was shown that αE-catenin is involved in regulating HIPPO signaling by binding with Yap.
αE-catenin deletion in the skin leads to keratinocyte hyperproliferation through HIPPO signaling inhibition. Furthermore, αE-catenin interacts with 14-3-3 protein and Yap and sequesters it in the cytoplasm, thereby preventing Yap translocation to the nucleus. The cardiospecific double knockout of αE- and αT-catenin in mice led to the activation of Yap-dependent transcription and cardiomyocyte proliferation. Furthermore, α-catenin modulates canonical WNT signaling. It prevents the interaction between the β-catenin/T-cell factor complex and DNA and stimulates β-catenin degradation. Recently we have shown that the loss of αE-catenin in embryonic heart enhances β-catenin and Yap transcriptional activity in cardiomyocytes, leas to extending fibrosis and hypertrophy and mice lethality at 11 month of age. However, α-Е-catenin role in adult heart development and function is far from understood.

Thus in our present study we have focused on detailed analysis of α-Е-catenin mutant hearts, namely we have analyzed the activity of most known hypertrophic signaling pathways: MAPK signaling, PK-В signaling,
PK-А – signaling.
In our experiment we have used α-Е-catenin conditional knockout and aMHC-Cre transgenic mice. This aMHC-Cre transgene elicits recombination in cardiac muscle but not in other organs.
αE-cateninflox/flox mice were obtained from Jackson Laboratories (Bar Harbor, ME, USA). To generate the cardiac-specific deletion of αE-catenin, we mated α-myosin heavy chain (aMHC)-Cre mice with floxed αE-catenin mice. We have utilized Western blot for analyses of total and phosphorylated level of protein involved in MAPK, PK-В and PK-А – signaling regulation. For this we have used left ventricles of mutant and control heart for protein isolation.

In result of our work we observed a two-fold increase in the levels of total Akt and pAkt at Ser473 in mutant hearts. The levels of pAkt at Thr308 were significantly lower in both mutant groups of mice. The levels of
pPK-A in both groups of mutant mice were significantly lower compared with controls. It’s important to note that, PK-A phosphorylates sarcomeric proteins, including titin. Titin is extremely important for heart contractions, and our finding suggest lower levels of titin phosphorylation and a weakening of cardiac contractions in mutant. Thus, this data also may indicate the violation of hemodynamic function in αE-catenin mutant hearts. Activation of the PK-В pathway and downregulation of the PK-А – signaling pathway are typical events that occur during heart failure. The analysis of MAPK1/3, another important factor that is involved in the development of heart pathology, revealed significantly lower pMAPK1/3 levels in αE-catenin-haploinsufficient hearts compared with controls. pMAPK1/3 levels were higher in hearts with homozygous knockout of αE-catenin compared with controls. It’s important to note, that both decreases and increases in MAPK1/3 have negative impacts on the heart and can provoke heart pathology.

Thus, we found that αE-catenin plays an important role in hypertrophic signaling pathways regulation. Our data indicate that αE-catenin depletion in the embryonic heart affects MAPK signaling, PK-В signaling and PK-А – signaling in adult heart and probably leads to heart failure.

References

ЛІТЕРАТУРА
1. Борьба с сердечно-сосудистыми заболеваниями URL: http://www.who.int/cardiovascular_diseases/ru/.
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3. Kontaridis M. I., Geladari E. V., Geladari C. V. Pathways to myocardial hypertrophy. Introduction to Translational Cardiovascular Research / Ed.D.V. Cokkins. Springer, Cham, 2015. P. 167-186.
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8. α-Catenin is a tumor suppressor that controls cell accumulation by regulating the localization and activity of the transcriptional coactivator yap1-catenin is a tumor suppressor that controls cell accumulation by regulating the localization and activity of the transcriptional coactivator Yap1 / Silvis M. R. et all. Science Signaling. 2011. Vol. 4, № 174. P. ra33.
9. α-Catenin interacts with APC to regulate β-catenin proteolysis and transcriptional repression of wnt target genes / Choi S. H. et all. Genes & Development. 2013. Vol. 27, № 22. P. 2473-2488.
10. α-catenins control cardiomyocyte proliferation by regulating yap activity / Li J. et. all. Circulation Research. 2015. Vol. 116, № 1. P. 70-79.
11. αE-catenin controls cerebral cortical size by regulating the hedgehog signaling pathway / Lien W.H. et. all. Science. 2006. Vol. 311, № 5767. P. 1609-1612.
12. β-Catenin accumulates in intercalated disks of hypertrophic cardiomyopathic hearts. / Masuelli L. et. all. Cardiovascular Research. 2003. Vol. 60, № 2. P. 376-387.
13. Cardiomyocyte-targeted overexpression of the coxsackie–adenovirus receptor causes a cardiomyopathy in association with β-catenin signaling / Caruso L. et all. Journal of Molecular and Cellular Cardiology. 2010. Vol. 48, № 6. P. 1194-1205.
14. Embryonically induced β-catenin haploinsufficiency attenuates postnatal heart development and causes violation of foetal genes program / Palchevska O. L. et all. Biopolymers and Cell. 2013. Vol. 29, № 2. P. 124-130.
15. Fukuda N., Wu Y., Nair P., Granzier H. L. Phosphorylation of titin modulates passive stiffness of cardiac muscle in a titin isoform-dependent manner. The Journal of General Physiology. 2005. Vol. 125, № 3. P. 257-271.
16. Chaanine A. H., Hajjar R. J. Akt signaling in the failing heart. European journal of heart failure. 2011. Vol. 13, № 8. P. 825-829.
17. Rose B. A., Force T., Wang Y. Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale. Physiological Reviews. 2010. Vol. 90, № 4. P. 1507-1546.
18. Genetic inhibition of cardiac erk1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo / Purcell N. H. et. all. Proceedings of the National Academy of Sciences of the United States of America. 2007. Vol. 104, № 35. P. 14074-14079.

REFERENCES
1. Bor’ba s serdechno-sosudistymi zabolevanijami URL: http://www.who.int/cardiovascular_diseases/ru/.
2. Bernardo B. C., Weeks K. L., Pretorius L., McMullen J. R. Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacology & Therapeutics. 2010. Vol. 128, № 1. P. 191-227.
3. Kontaridis M. I., Geladari E. V., Geladari C. V. Pathways to myocardial hypertrophy. Introduction to Translational Cardiovascular Research / Ed. D.V. Cokkins. Springer, Cham, 2015. P. 167-186.
4. Grigoryan T., Wend P., Klaus A., Birchmeier W. Deciphering the function of canonical wnt signals in development and disease: conditional loss- and gain-of-function mutations of beta-catenin in mice. Genes & Development. 2008. Vol. 22, № 17. P. 2308-2341.
5. Requirement for n-cadherin-catenin complex in heart development / Piven O. O. et. all. Experimental Biology and Medicine. 2011. Vol. 236, № 7. P. 816-822.
6. Balac’kij V. V., Pal’chevs’ka O. L., Macevich L. L., Pіven’ O. O. α-E-katenіn potencіjnij reguljator kanonіchnogo wnt ta hippo- signalіngіv u mіokardі. Vіsnik Ukrayins’kogo tovaristva genetikіv і selekcіonerіv. 2016. T. 14, № 2. S. 168-173.
7. Pіven’ O. O. Zmіni adgezivnih kompleksіv u tkaninі mіokarda jak odin іz mehanіzmіv porushen’ funkcії sercja. Ukrayins’kij kardіologіchnij zhurnal. 2010. № 6. S. 110-117.
8. α-Catenin is a tumor suppressor that controls cell accumulation by regulating the localization and activity of the transcriptional coactivator yap1-catenin is a tumor suppressor that controls cell accumulation by regulating the localization and activity of the transcriptional coactivator Yap1 / Silvis M. R. et all. Science Signaling. 2011. Vol. 4, № 174. P. ra33.
9. α-Catenin interacts with APC to regulate β-catenin proteolysis and transcriptional repression of wnt target genes / Choi S. H. et. al. Genes & Development. 2013. Vol. 27, № 22. P. 2473-2488.
10. α-catenins control cardiomyocyte proliferation by regulating yap activity / Li J. et all. Circulation Research. 2015. Vol. 116, № 1. P. 70-79.
11. αE-catenin controls cerebral cortical size by regulating the hedgehog signaling pathway / Lien W. H. et. al. Science. 2006. Vol. 311, № 5767. P. 1609-1612.
12. β-Catenin accumulates in intercalated disks of hypertrophic cardiomyopathic hearts. / Masuelli L. et all. Cardiovascular Research. 2003. Vol. 60, № 2. P. 376-387.
13. Cardiomyocyte-targeted overexpression of the coxsackie–adenovirus receptor causes a cardiomyopathy in association with β-catenin signaling / Caruso L. et. all. Journal of Molecular and Cellular Cardiology. 2010. Vol. 48, № 6. P. 1194-1205.
14. Embryonically induced β-catenin haploinsufficiency attenuates postnatal heart development and causes violation of foetal genes program / Palchevska O. L.. et. all. Biopolymers and Cell. 2013. Vol. 29, № 2. P. 124-130.
15. Fukuda N., Wu Y., Nair P., Granzier H. L. Phosphorylation of titin modulates passive stiffness of cardiac muscle in a titin isoform-dependent manner. The Journal of General Physiology. 2005. Vol. 125, № 3. P. 257-271.
16. Chaanine A. H., Hajjar R. J. Akt signaling in the failing heart. European journal of heart failure. 2011. Vol. 13, № 8. P. 825-829.
17. Rose B. A., Force T., Wang Y. Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale. Physiological Reviews. 2010. Vol. 90, № 4. P. 1507-1546.
18. Genetic inhibition of cardiac erk1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo / Purcell N. H. et all. Proceedings of the National Academy of Sciences of the United States of America. 2007. Vol. 104, № 35. P. 14074-14079.
How to Cite
Balatskyy, V. V., Macewicz, L. L., & Piven, O. O. (1). α-Е-CATENIN REGULATES HYPERTROPHIC SIGNALINGS IN HEART. Bulletin of Zaporizhzhia National University. Biological Sciences, (2), 42-48. Retrieved from http://journalsofznu.zp.ua/index.php/biology/article/view/95