Signalling function of β-catenin is important at early stages of adult heart pathological hypertrophy

  • O. O. Piven Institute of Molecular Biology and Genetics of NAS of Ukraine, Ukraine, 03680, Kyiv, Akademika Zabolotnoho str., 150
DOI: https://doi.org/10.7124/visnyk.utgis.14.1.543

Abstract

The spread of cardiovascular diseases, their significant threat to health and socio-economic burden result in considerable interest of scientists to this problem solution. Lately, not only investigations into new methods of diagnosis and treatment of cardiovascular disease, but also elucidation of the mechanisms underlying their occurrence and course become topical. The aim of our study was to investigate the signaling function of the canonical Wnt-signaling and b-catenin function in the development of pathological hypertrophy of the adult myocardium. Methods. Studies were conducted using transgenic mice BATGIRL and cultures of isolated cardiomyocytes. To induce pathological hypertrophy, lithium chloride and AnglI were used. Changes in the expression of hypertrophic genes and genes involved in the canonical Wnt-signaling were analyzed by real-time PCR and Western-blot analysis. Morphological studies and X-gal staining were performed. Results. Upon the action of hypertrophic stimuli the activation of b-catenin signaling function is shown to occur in the early stages of observation, as evidenced by X-gal staining and changes in gene-targets expression of this signaling (c-Fos, c-Myc, CyclinD1 and TCF-4). There was also observed an increase in the content of activated b-catenin and phosphorylated GSK3b proteins within a day after the action of angiotensin and lithium chloride in the culture of isolated cardiomyocytes. Conclusions. With the development of pathological hypertrophy due to chronic high blood pressure, there occurs the activation of many signal-regulatory mechanisms of cardiomyocytes and one of them is the canonical Wnt-signaling. However, the activation of the canonical Wnt-signaling and β-catenin, in particular, is the early event and obviously essential to run the genetic program of myocardium remodeling.

Keywords: β-catenin, hypertrophy, Wnt-signaling, gene expression, myocardium.

References

Cardiovascular diseases. http://www.who.int/cardiovascular_diseases/ru/

Bianca C. Bernardo, Kate L. Weeks, Lynette Pretorius, Julie R. McMullen. Molecular distinction between physiological and pathological cardiac hypertrophy: Experimental findings and therapeutic strategies. J. Pharmacol. Exp. Ther. 2010. Vol. 128(1). P. 191–227. doi: 10.1016/j.pharmthera.2010.04.005

Kontaridis M.I., Geladari E.V., Geladari C.V. Pathways to myocardial hypertrophy. In: Introduction to translational cardiovascular research. Ed. Cokkinos D.V. Springer, 2014. P. 167-186. doi: 10.1007/978-3-319-08798-6_10

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 b-catenin in mice. Genes Dev. 2008. Vol. 22(17). P. 2308–2341. doi: 10.1101/gad.1686208

Deb A. Cell-cell interaction in the heart via Wnt/β-catenin pathway after cardiac injury. Cardiovasc. Res. 2014. Vol 102(2). P. 214-223. doi: 10.1093/cvr/cvu054

Clevers H. Wnt/β-catenin signaling in development and disease. Cell. 2006. Vol. 127(3). P. 470-480. doi: 10.1186/2045-3701-2-14

Chen X., Shevtsov S.P., Hsich E. et al. The beta-catenin/T-cell factor/lymphocyte enhancer factor signaling pathway is required for normal and stress induced cardiac hypertrophy. Mol. Cell. Biol. 2006. Vol. 26(12). P. 4462–4473. doi: 10.1128/MCB.02157-05

Qu J., Zhou J., Yi X.P., Dong B., Zheng H., Miller L.M., Wang X., Schneider M.D., Li F. Cardiac-specific haploinsufficiency of beta-catenin attenuates cardiac hypertrophy but enhances foetal gene expression in response to aortic constriction. J. Mol. Cell. Cardiol. 2007. Vol. 43(3). P. 319–326. doi: 10.1016/j.yjmcc.2007.06.006

Hahn J.Y., Cho H.J., Bae J.W., Yuk H.S., Kim K.I., Park K.W., Koo B.K., Chae I.H., Shin C.S., Oh B.H., Choi Y.S., Park Y.B., Kim H.S. β-Catenin overexpression reduces myocardial infarct size through differential effects on cardiomyocytes and cardiac fibroblasts. J. Bio. Chem. 2006. Vol. 281(41). P. 30979–30989. doi: 10.1074/jbc.M603916200

Malekar P., Hagenmueller M., Anyanwu A., Buss S., Streit M.R., Weiss C.S., Wolf D., Riffel J., Bauer A., Katus H.A., Hardt S.E. Wnt signaling is critical for maladaptive cardiac hypertrophy and accelerates myocardial remodeling. Hypertension. 2010. Vol. 55. P. 939–945. doi: 10.1161/hypertensionaha.109.141127

Baurand A., Zelarayan L., Betney R., Gehrke C., Dunger S., Noack C., Busjahn A., Huelsken J., Taketo M.M., Birchmeier W., Dietz R., Bergmann M.W. Beta-catenin downregulation is required for adaptive cardiac remodelling. Circ. Res. 2007. Vol. 100(9). P. 1353–1362. doi: 10.1161/01.res.0000266605.63681.5a

Al Alam D, Green M, Tabatabai Irani R, Parsa S, Danopoulos S, Sala FG, Branch J, El Agha E, Tiozzo C, Voswinckel R, Jesudason EC, Warburton D, Bellusci S. Contrasting expression of canonical wnt signaling reporters topgal, batgal and axin2(lacz) during murine lung development and repair. PloS one. 2011. Vol 6(8). P. 23139. doi: 10.1371/journal.pone.0023139

Kostetskii I., Moore R., Kemler R., Radice G.L. Differential adhesion leads to segregation and exclusion of N-cadherin-deficient cells in chimeric embryos. Dev. Biol. 2001. Vol. 234(1). P. 72–79. doi: 10.1006/dbio.2001.0250

Piven O., Kostetskii I., Macewicz L., Kolomijec Y., Radice G., Lukash L. Requirement for N-cadherin-catenin complex in heart development. Exp. Biol. Med. 2011. Vol. 236(7). P. 816-822. doi: 10.1258/ebm.2011.010362

O’Connell T.D., Ni Y.G., Lin K.-M., Han H., Yan Zh. Isolation and culture of adult mouse cardiac myocytes for signaling studies. AfCS Research Reports. 2003. Vol. 1(5). P. 1-8.

Maniatis T., Fritsch E. F., Sambrook J. Molecular cloning: a laboratory manual. Moskva: Mir, 1984. 425 p.

Laemmli U.K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970. Vol. 227(5259). P. 680–685. doi: 10.1038/227680a0

Nagy A., Gertsenstein M., Vintersten K., Behringer R. Manipulating the mouse embryo: a laboratory manual. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 2003. 814 p.

Li J., Swope D., Raess N., Cheng L., Muller E.J., Radice G.L. Cardiac tissue-restricted deletion of plakoglobin results in progressive cardiomyopathy and activation of {beta}-catenin signaling. Mol. Cell. Biol. 2011. Vol. 31(6). P. 134–144. doi: 10.1128/MCB.01025-10

Watkins S.J., Borthwick G.M., Oakenfull R., Robson A., Arthur H.M. Angiotensin ii-induced cardiomyocyte hypertrophy in vitro is tak1-dependent and smad2/3-independent. Hypertens. Res. 2012. Vol. 35. P. 393–398. doi: 10.1038/hr.2011.196

Yamamoto F, Yamamoto H. Effect of inhibition of glycogen synthase kinase-3 on cardiac hypertrophy during acute pressure overload. Gen. Thorac. Cardiovasc. Surg. 2010. Vol. 58(6). P. 263–264. doi: 10.1007/s11748-009-0562-6

Archbold H.C., Yang Y.X., Chen L., Cadigan K.M. Wnt/b-catenin pathway: regulation of transcription by the Wnt. How do they do? Acta Physiol. 2012. Vol. 204(1). P.74–109. doi: 10.1111/j.1748-1716.2011.02293.x

Filipovich A., Gehrke I., Poll-Wolbeck S.J., Kreuzer K.A. Physiological inhibitors of Wnt signaling. Eur. J. Haematol. 2011 – Vol. 86(6). P.453–465. doi: 10.1111/j.1600-0609.2011.01592.x