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Published in: Cardiovascular Toxicology 1/2015

01-01-2015

H2O2 Induces Myocardial Hypertrophy in H9c2 Cells: A Potential Role of Ube3a

Authors: Rui Song, Jie Zhang, Lijuan Zhang, Guanghua Wang, Da Wo, Jian Feng, Xucheng Li, Jue Li

Published in: Cardiovascular Toxicology | Issue 1/2015

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Abstract

Myocardial hypertrophy that often leads to eventual heart failure is a leading cause of mortality worldwide. While both apoptosis and cell proliferation have been reported to play an important part in heart failure, its exact triggering mechanism is still unclear. Reports have shown that low concentrations of H2O2 (10–30 µM) can induce myocardial hypertrophy without affecting survival. The ubiquitin ligase Ube3a has been reported to have a close affiliation with Angelman syndrome; but many ubiquitin ligases have been reported in a variety of cardiovascular conditions including myocardial hypertrophy. However, the relationship between Ube3a and myocardial hypertrophy has never been reported in literature. The rat cardiac myoblast cell line H9c2 and primary neonatal cardiomyocytes showed similar hypertrophic responses in vitro. In this report, we utilized H2O2 treatment on H9c2 cells to induce myocardial hypertrophy and determined the relationship between Ube3a and myocardial hypertrophy. Our results showed that 10–20 μM H2O2 can induce myocardial hypertrophy without affecting cell viability and inducing cell apoptosis, while the corresponding transcription and translation levels of Ube3a are significantly increased during the process. Therefore, these findings underline that Ube3a may play an important role in myocardial hypertrophy.
Literature
1.
go back to reference Sarkar, S., Leaman, D. W., Gupta, S., Sil, P., Young, D., Morehead, A., et al. (2004). Cardiac overexpression of myotrophin triggers myocardial hypertrophy and heart failure in transgenic mice. Journal of Biological Chemistry, 279(19), 20422–20434.CrossRefPubMed Sarkar, S., Leaman, D. W., Gupta, S., Sil, P., Young, D., Morehead, A., et al. (2004). Cardiac overexpression of myotrophin triggers myocardial hypertrophy and heart failure in transgenic mice. Journal of Biological Chemistry, 279(19), 20422–20434.CrossRefPubMed
2.
go back to reference Schaub, M. C., Hefti, M. A., & Zaugg, M. (2006). Integration of calcium with the signaling network in cardiac myocytes. Journal of Molecular and Cellular Cardiology, 41(2), 183–214.CrossRefPubMed Schaub, M. C., Hefti, M. A., & Zaugg, M. (2006). Integration of calcium with the signaling network in cardiac myocytes. Journal of Molecular and Cellular Cardiology, 41(2), 183–214.CrossRefPubMed
3.
go back to reference Pimentel, D. R., Amin, J. K., Xiao, L., Miller, T., Viereck, J., Oliver-Krasinski, J., et al. (2001). Reactive oxygen species mediate amplitude-dependent hypertrophic and apoptotic responses to mechanical stretch in cardiac myocytes. Circulation Research, 89(5), 453–460.CrossRefPubMed Pimentel, D. R., Amin, J. K., Xiao, L., Miller, T., Viereck, J., Oliver-Krasinski, J., et al. (2001). Reactive oxygen species mediate amplitude-dependent hypertrophic and apoptotic responses to mechanical stretch in cardiac myocytes. Circulation Research, 89(5), 453–460.CrossRefPubMed
4.
go back to reference Kwon, S. H., Pimentel, D. R., Remondino, A., Sawyer, D. B., & Colucci, W. S. (2003). H(2)O(2) regulates cardiac myocyte phenotype via concentration-dependent activation of distinct kinase pathways. Journal of Molecular and Cellular Cardiology, 35(6), 615–621.CrossRefPubMed Kwon, S. H., Pimentel, D. R., Remondino, A., Sawyer, D. B., & Colucci, W. S. (2003). H(2)O(2) regulates cardiac myocyte phenotype via concentration-dependent activation of distinct kinase pathways. Journal of Molecular and Cellular Cardiology, 35(6), 615–621.CrossRefPubMed
5.
go back to reference Shi, P. P., Cao, X. R., Sweezer, E. M., Kinney, T. S., Williams, N. R., Husted, R. F., et al. (2008). Salt-sensitive hypertension and cardiac hypertrophy in mice deficient in the ubiquitin ligase Nedd4-2. American Journal of Physiology-Renal Physiology, 295(2), F462–F470.CrossRefPubMedCentralPubMed Shi, P. P., Cao, X. R., Sweezer, E. M., Kinney, T. S., Williams, N. R., Husted, R. F., et al. (2008). Salt-sensitive hypertension and cardiac hypertrophy in mice deficient in the ubiquitin ligase Nedd4-2. American Journal of Physiology-Renal Physiology, 295(2), F462–F470.CrossRefPubMedCentralPubMed
6.
go back to reference Li, H. H., Willis, M. S., Lockyer, P., Miller, N., Mcdonough, H., Glass, D. J., et al. (2007). Atrogin-1 inhibits Akt-dependent cardiac hypertrophy in mice via ubiquitin-dependent coactivation of Forkhead proteins. Journal of Clinical Investigation, 117(11), 3211–3223.CrossRefPubMedCentralPubMed Li, H. H., Willis, M. S., Lockyer, P., Miller, N., Mcdonough, H., Glass, D. J., et al. (2007). Atrogin-1 inhibits Akt-dependent cardiac hypertrophy in mice via ubiquitin-dependent coactivation of Forkhead proteins. Journal of Clinical Investigation, 117(11), 3211–3223.CrossRefPubMedCentralPubMed
7.
go back to reference Weekes, J., Morrison, K., Mullen, A., Wait, R., Barton, P., & Dunn, M. J. (2003). Hyperubiquitination of proteins in dilated cardiomyopathy. Proteomics, 3(2), 208–216.CrossRefPubMed Weekes, J., Morrison, K., Mullen, A., Wait, R., Barton, P., & Dunn, M. J. (2003). Hyperubiquitination of proteins in dilated cardiomyopathy. Proteomics, 3(2), 208–216.CrossRefPubMed
8.
go back to reference Matsuura, T., Sutcliffe, J. S., Fang, P., Galjaard, R. J., Jiang, Y. H., Benton, C. S., et al. (1997). De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nature Genetics, 15(1), 74–77.CrossRefPubMed Matsuura, T., Sutcliffe, J. S., Fang, P., Galjaard, R. J., Jiang, Y. H., Benton, C. S., et al. (1997). De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nature Genetics, 15(1), 74–77.CrossRefPubMed
9.
go back to reference Huang, H. S., Allen, J. A., Mabb, A. M., King, I. F., Miriyala, J., Taylor-Blake, B., et al. (2012). Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature, 481(7380), 185–189.CrossRef Huang, H. S., Allen, J. A., Mabb, A. M., King, I. F., Miriyala, J., Taylor-Blake, B., et al. (2012). Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature, 481(7380), 185–189.CrossRef
10.
go back to reference Burger, J., Horn, D., Tonnies, H., Neitzel, H., & Reis, A. (2002). Familial interstitial 570 kbp deletion of the UBE3A gene region causing Angelman syndrome but not Prader–Willi syndrome. American Journal of Medical Genetics, 111(3), 233–237.CrossRefPubMed Burger, J., Horn, D., Tonnies, H., Neitzel, H., & Reis, A. (2002). Familial interstitial 570 kbp deletion of the UBE3A gene region causing Angelman syndrome but not Prader–Willi syndrome. American Journal of Medical Genetics, 111(3), 233–237.CrossRefPubMed
11.
go back to reference Veenstra-Vanderweele, J., Gonen, D., Leventhal, B. L., & Cook, E. J. (1999). Mutation screening of the UBE3A/E6-AP gene in autistic disorder. Molecular Psychiatry, 4(1), 64–67.CrossRefPubMed Veenstra-Vanderweele, J., Gonen, D., Leventhal, B. L., & Cook, E. J. (1999). Mutation screening of the UBE3A/E6-AP gene in autistic disorder. Molecular Psychiatry, 4(1), 64–67.CrossRefPubMed
12.
go back to reference Maheshwari, M., Samanta, A., Godavarthi, S. K., Mukherjee, R., & Jana, N. R. (2012). Dysfunction of the ubiquitin ligase Ube3a may be associated with synaptic pathophysiology in a mouse model of Huntington disease. Journal of Biological Chemistry, 287(35), 29949–29957.CrossRefPubMedCentralPubMed Maheshwari, M., Samanta, A., Godavarthi, S. K., Mukherjee, R., & Jana, N. R. (2012). Dysfunction of the ubiquitin ligase Ube3a may be associated with synaptic pathophysiology in a mouse model of Huntington disease. Journal of Biological Chemistry, 287(35), 29949–29957.CrossRefPubMedCentralPubMed
13.
go back to reference Swynghedauw, B., Besse, S., Assayag, P., Carre, F., Chevalier, B., Charlemagne, D., et al. (1995). Molecular and cellular biology of the senescent hypertrophied and failing heart. American Journal of Cardiology, 76(13), 2D–7D.CrossRefPubMed Swynghedauw, B., Besse, S., Assayag, P., Carre, F., Chevalier, B., Charlemagne, D., et al. (1995). Molecular and cellular biology of the senescent hypertrophied and failing heart. American Journal of Cardiology, 76(13), 2D–7D.CrossRefPubMed
14.
go back to reference Francis, G. S., Mcdonald, K., Chu, C., & Cohn, J. N. (1995). Pathophysiologic aspects of end-stage heart failure. American Journal of Cardiology, 75(3), 11A–16A.CrossRefPubMed Francis, G. S., Mcdonald, K., Chu, C., & Cohn, J. N. (1995). Pathophysiologic aspects of end-stage heart failure. American Journal of Cardiology, 75(3), 11A–16A.CrossRefPubMed
15.
go back to reference Willis, M. S., Ike, C., Li, L., Wang, D. Z., Glass, D. J., & Patterson, C. (2007). Muscle ring finger 1, but not muscle ring finger 2, regulates cardiac hypertrophy in vivo. Circulation Research, 100(4), 456–459.CrossRefPubMedCentralPubMed Willis, M. S., Ike, C., Li, L., Wang, D. Z., Glass, D. J., & Patterson, C. (2007). Muscle ring finger 1, but not muscle ring finger 2, regulates cardiac hypertrophy in vivo. Circulation Research, 100(4), 456–459.CrossRefPubMedCentralPubMed
16.
go back to reference Willis, M. S., Wadosky, K. M., Rodriguez, J. E., Schisler, J. C., Lockyer, P., Hilliard, E. G., et al. (2014). Muscle ring finger 1 and muscle ring finger 2 are necessary but functionally redundant during developmental cardiac growth and regulate E2F1-mediated gene expression in vivo. Cell Biochemistry and Function, 32(1), 39–50.CrossRefPubMedCentralPubMed Willis, M. S., Wadosky, K. M., Rodriguez, J. E., Schisler, J. C., Lockyer, P., Hilliard, E. G., et al. (2014). Muscle ring finger 1 and muscle ring finger 2 are necessary but functionally redundant during developmental cardiac growth and regulate E2F1-mediated gene expression in vivo. Cell Biochemistry and Function, 32(1), 39–50.CrossRefPubMedCentralPubMed
17.
go back to reference Bodine, S. C., Latres, E., Baumhueter, S., Lai, V. K., Nunez, L., Clarke, B. A., et al. (2001). Identification of ubiquitin ligases required for skeletal muscle atrophy. Science, 294(5547), 1704–1708.CrossRefPubMed Bodine, S. C., Latres, E., Baumhueter, S., Lai, V. K., Nunez, L., Clarke, B. A., et al. (2001). Identification of ubiquitin ligases required for skeletal muscle atrophy. Science, 294(5547), 1704–1708.CrossRefPubMed
18.
go back to reference Ni, Y. G., Berenji, K., Wang, N., Oh, M., Sachan, N., Dey, A., et al. (2006). Foxo transcription factors blunt cardiac hypertrophy by inhibiting calcineurin signaling. Circulation, 114(11), 1159–1168.CrossRefPubMedCentralPubMed Ni, Y. G., Berenji, K., Wang, N., Oh, M., Sachan, N., Dey, A., et al. (2006). Foxo transcription factors blunt cardiac hypertrophy by inhibiting calcineurin signaling. Circulation, 114(11), 1159–1168.CrossRefPubMedCentralPubMed
19.
go back to reference Li, H. H., Kedar, V., Zhang, C., Mcdonough, H., Arya, R., Wang, D. Z., et al. (2004). Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex. Journal of Clinical Investigation, 114(8), 1058–1071.CrossRefPubMedCentralPubMed Li, H. H., Kedar, V., Zhang, C., Mcdonough, H., Arya, R., Wang, D. Z., et al. (2004). Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex. Journal of Clinical Investigation, 114(8), 1058–1071.CrossRefPubMedCentralPubMed
20.
go back to reference Xie, P., Guo, S., Fan, Y., Zhang, H., Gu, D., & Li, H. (2009). Atrogin-1/MAFbx enhances simulated ischemia/reperfusion-induced apoptosis in cardiomyocytes through degradation of MAPK phosphatase-1 and sustained JNK activation. Journal of Biological Chemistry, 284(9), 5488–5496.CrossRefPubMed Xie, P., Guo, S., Fan, Y., Zhang, H., Gu, D., & Li, H. (2009). Atrogin-1/MAFbx enhances simulated ischemia/reperfusion-induced apoptosis in cardiomyocytes through degradation of MAPK phosphatase-1 and sustained JNK activation. Journal of Biological Chemistry, 284(9), 5488–5496.CrossRefPubMed
21.
go back to reference Balasubramanian, S., Mani, S., Shiraishi, H., Johnston, R. K., Yamane, K., Willey, C. D., et al. (2006). Enhanced ubiquitination of cytoskeletal proteins in pressure overloaded myocardium is accompanied by changes in specific E3 ligases. Journal of Molecular and Cellular Cardiology, 41(4), 669–679.CrossRefPubMed Balasubramanian, S., Mani, S., Shiraishi, H., Johnston, R. K., Yamane, K., Willey, C. D., et al. (2006). Enhanced ubiquitination of cytoskeletal proteins in pressure overloaded myocardium is accompanied by changes in specific E3 ligases. Journal of Molecular and Cellular Cardiology, 41(4), 669–679.CrossRefPubMed
22.
go back to reference Potts, M. B., Vaughn, A. E., Mcdonough, H., Patterson, C., & Deshmukh, M. (2005). Reduced Apaf-1 levels in cardiomyocytes engage strict regulation of apoptosis by endogenous XIAP. Journal of Cell Biology, 171(6), 925–930.CrossRefPubMedCentralPubMed Potts, M. B., Vaughn, A. E., Mcdonough, H., Patterson, C., & Deshmukh, M. (2005). Reduced Apaf-1 levels in cardiomyocytes engage strict regulation of apoptosis by endogenous XIAP. Journal of Cell Biology, 171(6), 925–930.CrossRefPubMedCentralPubMed
23.
go back to reference Rafiq, K., Guo, J., Vlasenko, L., Guo, X., Kolpakov, M. A., Sanjay, A., et al. (2012). c-Cbl ubiquitin ligase regulates focal adhesion protein turnover and myofibril degeneration induced by neutrophil protease cathepsin G. Journal of Biological Chemistry, 287(8), 5327–5339.CrossRefPubMedCentralPubMed Rafiq, K., Guo, J., Vlasenko, L., Guo, X., Kolpakov, M. A., Sanjay, A., et al. (2012). c-Cbl ubiquitin ligase regulates focal adhesion protein turnover and myofibril degeneration induced by neutrophil protease cathepsin G. Journal of Biological Chemistry, 287(8), 5327–5339.CrossRefPubMedCentralPubMed
24.
go back to reference Siwik, D. A., Tzortzis, J. D., Pimental, D. R., Chang, D. L., Pagano, P. J., Singh, K., et al. (1999). Inhibition of copper-zinc superoxide dismutase induces cell growth, hypertrophic phenotype, and apoptosis in neonatal rat cardiac myocytes in vitro. Circulation Research, 85(2), 147–153.CrossRefPubMed Siwik, D. A., Tzortzis, J. D., Pimental, D. R., Chang, D. L., Pagano, P. J., Singh, K., et al. (1999). Inhibition of copper-zinc superoxide dismutase induces cell growth, hypertrophic phenotype, and apoptosis in neonatal rat cardiac myocytes in vitro. Circulation Research, 85(2), 147–153.CrossRefPubMed
25.
go back to reference Chen, Q. M., Tu, V. C., Wu, Y., & Bahl, J. J. (2000). Hydrogen peroxide dose dependent induction of cell death or hypertrophy in cardiomyocytes. Archives of Biochemistry and Biophysics, 373(1), 242–248.CrossRefPubMed Chen, Q. M., Tu, V. C., Wu, Y., & Bahl, J. J. (2000). Hydrogen peroxide dose dependent induction of cell death or hypertrophy in cardiomyocytes. Archives of Biochemistry and Biophysics, 373(1), 242–248.CrossRefPubMed
Metadata
Title
H2O2 Induces Myocardial Hypertrophy in H9c2 Cells: A Potential Role of Ube3a
Authors
Rui Song
Jie Zhang
Lijuan Zhang
Guanghua Wang
Da Wo
Jian Feng
Xucheng Li
Jue Li
Publication date
01-01-2015
Publisher
Springer US
Published in
Cardiovascular Toxicology / Issue 1/2015
Print ISSN: 1530-7905
Electronic ISSN: 1559-0259
DOI
https://doi.org/10.1007/s12012-014-9264-0

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