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Licensed Unlicensed Requires Authentication Published by De Gruyter June 23, 2017

The role of sirtuins in mitochondrial function and doxorubicin-induced cardiac dysfunction

  • Vernon W. Dolinsky EMAIL logo
From the journal Biological Chemistry

Abstract

Anthracycline chemotherapeutics such as doxorubicin continue to be important treatments for many cancers. Through improved screening and therapy, more patients are surviving and living longer after the diagnosis of their cancer. However, anthracyclines are associated with both short- and long-term cardiotoxic effects. Doxorubicin-induced mitochondrial dysfunction is a central mechanism in the cardiotoxic effects of doxorubicin that contributes to impaired cardiac energy levels, increased reactive oxygen species production, cardiomyocyte apoptosis and the decline in cardiac function. Sirtuins are protein deacetylases that are activated by low energy levels and stimulate energy production through their activation of transcription factors and enzymatic regulators of cardiac energy metabolism. In addition, sirtuins activate oxidative stress resistance pathways. SIRT1 and SIRT3 are expressed at high levels in the cardiomyocyte. This review examines the function of sirtuins in the regulation of cardiac mitochondrial function, with a focus on their role in heart failure and an emphasis on their effects on doxorubicin-induced cardiotoxicity. We discuss the potential for sirtuin activation in combination with anthracycline chemotherapy in order to mitigate its cardiotoxic side-effects without reducing the antineoplastic activity of anthracyclines.

Acknowledgments

The author thanks Mr. Kyle Cheung for preparing the figures in the manuscript. This work was supported by a research grants to V.W.D. from the Heart and Stroke Foundation of Canada (HSFC), Grant #G16-0001399. V.W.D. is the Ken Hughes Young Investigator and the Dr. J.A. Moorhouse Fellow of the Diabetes Foundation of Manitoba.

References

Abdel-aleem, S., el-Merzabani, M.M., Sayed-Ahmed, M., Taylor, D.A., and Lowe, J.E. (1997). Acute and chronic effects of adriamycin on fatty acid oxidation in isolated cardiac myocytes. J. Mol. Cell. Cardiol. 29, 789–797.10.1006/jmcc.1996.0323Search in Google Scholar PubMed

Ahn, B.H., Kim, H.S., Song, S., Lee, I.H., Liu, J., Vassilopoulos, A., Deng, C.X., and Finkel, T. (2008). A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc. Natl. Acad. Sci. USA 105, 14447–14452.10.1073/pnas.0803790105Search in Google Scholar PubMed PubMed Central

Alcendor, R.R., Kirshenbaum, L.A., Imai, S., Vatner, S.F., and Sadoshima, J. (2004). Silent information regulator 2alpha, a longevity factor and class III histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytes. Circ. Res. 95, 971–980.10.1161/01.RES.0000147557.75257.ffSearch in Google Scholar PubMed

Alcendor, R.R., Gao, S., Zhai, P., Zablocki, D., Holle, E., Yu, X., Tian, B., Wagner, T., Vatner, S.F., and Sadoshima, J. (2007). Sirt1 regulates aging and resistance to oxidative stress in the heart. Circ. Res. 100, 1512–1521.10.1161/01.RES.0000267723.65696.4aSearch in Google Scholar PubMed

Alhazzazi, T.Y., Kamarajan, P., Joo, N., Huang, J.Y., Verdin, E., D’silva, N.J., and Kapila, Y.L. (2011). Sirtuin-3 (SIRT3), a novel potential therapeutic target for oral cancer. Cancer 117, 1670–1678.10.1002/cncr.25676Search in Google Scholar PubMed PubMed Central

Allard, M.F. (2004). Energy substrate metabolism in cardiac hypertrophy. Curr. Hypertens. Rep. 6, 430–435.10.1007/s11906-004-0036-2Search in Google Scholar PubMed

Arena, E., D’Alessandro, N., Dusonchet, L., Geraci, M., Rausa, L., and Sanguedolce, R. (1979). Repair kinetics of DNA, RNA and proteins in the tissues of mice treated with DOX. Arzneimittel-Forschung 29, 901–902.Search in Google Scholar

Arola, O.J., Saraste, A., Pulkki, K., Kallajoki, M., Parvinen, M., and Voipio-Pulkki, L.M. (2000). Acute DOX cardiotoxicity involves cardiomyocyte apoptosis. Cancer Res. 60, 1789–1792.Search in Google Scholar

Ashraf, N., Zino, S., Macintyre, A., Kingsmore, D., Payne, A.P., George, W.D., and Shiels, P.G. (2006). Altered sirtuin expression is associated with node-positive breast cancer. Br. J. Cancer 95, 1056–1061.10.1038/sj.bjc.6603384Search in Google Scholar PubMed PubMed Central

Bao, J., Lu, Z., Joseph, J.J., Carabenciov, D., Dimond, C.C., Pang, L., Samsel, L., McCoy, J.P., Leclerc, J., Nguyen, P., et al. (2010a). Characterization of the murine SIRT3 mitochondrial localization sequence and comparison of mitochondrial enrichment and deacetylase activity of long and short SIRT3 isoforms. J. Cell. Biochem. 110, 238–247.10.1002/jcb.22531Search in Google Scholar PubMed PubMed Central

Bao, J., Scott, I., Lu, Z., Pang, L., Dimond, C.C., Gius, D., and Sack, M.N. (2010b). SIRT3 is regulated by nutrient excess and modulates hepatic susceptibility to lipotoxicity. Free Radic. Biol. Med. 49, 1230–1237.10.1016/j.freeradbiomed.2010.07.009Search in Google Scholar PubMed PubMed Central

Baur, J.A., Pearson, K.J., Price, N.L., Jamieson, H.A., Lerin, C., Kalra, A., Prabhu, V.V., Allard, J.S., Lopez-Lluch, G., Lewis, K., et al. (2006). Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337–342.10.1038/nature05354Search in Google Scholar PubMed PubMed Central

Beadle, R.M. and Frenneaux, M. (2010). Modification of myocardial substrate utilisation: a new therapeutic paradigm in cardiovascular disease. Heart 96, 824–830.10.1136/hrt.2009.190256Search in Google Scholar

Bell, E.L., Emerling, B.M., Ricoult, S.J., and Guarente, L. (2011). SirT3 suppresses hypoxia inducible factor 1alpha and tumor growth by inhibiting mitochondrial ROS production. Oncogene 30, 2986–2996.10.1038/onc.2011.37Search in Google Scholar

Benigni, A., Corna, D., Zoja, C., Sonzogni, A., Latini, R., Salio, M., Conti, S., Rottoli, D., Longaretti, L., Cassis, P., et al. (2009). Disruption of the Ang II type 1 receptor promotes longevity in mice. J. Clin. Invest. 119, 524–530.10.1172/JCI36703Search in Google Scholar

Berthiaume, J.M. and Wallace, K.B. (2007). Persistent alterations to the gene expression profile of the heart subsequent to chronic DOX treatment. Cardiovasc. Toxicol. 7, 178–191.10.1007/s12012-007-0026-0Search in Google Scholar

Bharathi, S.S., Zhang, Y., Mohsen, A.W., Uppala, R., Balasubramani, M., Schreiber, E., Uechi, G., Beck, M.E., Rardin, M.J., Vockley, J., et al. (2013). Sirtuin 3 (SIRT3) protein regulates long-chain acyl-CoA dehydrogenase by deacetylating conserved lysines near the active site. J. Biol. Chem. 288, 33837–33847.10.1074/jbc.M113.510354Search in Google Scholar

Bianchi, C., Bagnato, A., Paggi, M.G., and Floridi, A. (1987). Effect of adriamycin on electron transport in rat heart, liver, and tumor mitochondria. Exper. Mol. Pathol. 46, 123–135.10.1016/0014-4800(87)90036-0Search in Google Scholar

Biel, T.G., Lee, S., Flores-Toro, J.A., Dean, J.W., Go, K.L., Lee, M.H., Law, B.K., Law, M.E., Dunn, W.A., Zendejas, I., et al. (2016). Sirtuin 1 suppresses mitochondrial dysfunction of ischemic mouse livers in a mitofusin 2-dependent manner. Cell Death Differ. 23, 279–290.10.1038/cdd.2015.96Search in Google Scholar

Bordoni, A., Biagi, P., and Hrelia, S. (1999). The impairment of essential fatty acid metabolism as a key factor in DOX-induced damage in cultured rat cardiomyocytes. Biochim. Biophys. Acta 1440, 100–106.10.1016/S1388-1981(99)00113-4Search in Google Scholar

Bradshaw, P.T., Stevens, J., Khankari, N., Teitelbaum, S.L., Neugut, A.I., and Gammon, M.D. (2016). Cardiovascular disease mortality among breast cancer survivors. Epidemiology 27, 6–13.10.1097/EDE.0000000000000394Search in Google Scholar PubMed PubMed Central

Bugger, H., Schwarzer, M., Chen, D., Schrepper, A., Amorim, P.A., Schoepe, M., Nguyen, T.D., Mohr, F.W., Khalimonchuk, O., Weimer, B.C., et al. (2010). Proteomic remodelling of mitochondrial oxidative pathways in pressure overload-induced heart failure. Cardiovasc. Res. 85, 376–384.10.1093/cvr/cvp344Search in Google Scholar PubMed

Bui, A.L., Horwich, T.B., and Fonarow, G.C. (2011). Epidemiology and risk profile of heart failure. Nat. Rev. Cardiol. 8, 30–41.10.1038/nrcardio.2010.165Search in Google Scholar PubMed PubMed Central

Cadete, V.J., Deschenes, S., Cuillerier, A., Brisebois, F., Sugiura, A., Vincent, A., Turnbull, D., Picard, M., McBride, H.M., and Burelle, Y. (2016). Formation of mitochondrial-derived vesicles is an active and physiologically relevant mitochondrial quality control process in the cardiac system. J. Physiol. 594, 5343–5362.10.1113/JP272703Search in Google Scholar PubMed PubMed Central

Cappetta, D., Esposito, G., Piegari, E., Russo, R., Ciuffreda, L.P., Rivellino, A., Berrino, L., Rossi, F., De Angelis, A., and Urbanek, K. (2016). SIRT1 activation attenuates diastolic dysfunction by reducing cardiac fibrosis in a model of anthracycline cardiomyopathy. Int. J. Cardiol. 205, 99–110.10.1016/j.ijcard.2015.12.008Search in Google Scholar PubMed

Chan, N.C., Salazar, A.M., Pham, A.H., Sweredoski, M.J., Kolawa, N.J., Graham, R.L., Hess, S., and Chan, D.C. (2011). Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum. Mol. Genet. 20, 1726–1737.10.1093/hmg/ddr048Search in Google Scholar PubMed PubMed Central

Chatterjee, K., Zhang, J., Honbo, N., and Karliner, J.S. (2010). DOX cardiomyopathy. Cardiol. 115, 155–162.10.1159/000265166Search in Google Scholar PubMed PubMed Central

Chen, Y., Zhang, J., Lin, Y., Lei, Q., Guan, K.L., Zhao, S., and Xiong, Y. (2011). Tumour suppressor SIRT3 deacetylates and activates manganese superoxide dismutase to scavenge ROS. EMBO Rep. 12, 534–541.10.1038/embor.2011.65Search in Google Scholar PubMed PubMed Central

Chen, J., Long, J.B., Hurria, A., Owusu, C., Steingart, R.M., and Gross, C.P. (2012). Incidence of heart failure or cardiomyopathy after adjuvant trastuzumab therapy for breast cancer. J. Am. Coll. Cardiol. 60, 2504–2512.10.1016/j.jacc.2012.07.068Search in Google Scholar PubMed

Chen, T., Liu, J., Li, N., Wang, S., Liu, H., Li, J., Zhang, Y., and Bu, P. (2015). Mouse SIRT3 attenuates hypertrophy-related lipid accumulation in the heart through the deacetylation of LCAD. PLoS One 10, e0118909.10.1371/journal.pone.0118909Search in Google Scholar PubMed PubMed Central

Cheng, H.L., Mostoslavsky, R., Saito, S., Manis, J.P., Gu, Y., Patel, P., Bronson, R., Appella, E., Alt, F.W., and Chua, K.F. (2003). Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc. Natl. Acad. Sci. USA 100, 10794–10799.10.1073/pnas.1934713100Search in Google Scholar PubMed PubMed Central

Cheung, K.G., Cole, L.K., Xiang, B., Chen, K., Ma, X., Myal, Y., Hatch, G.M., Tong, Q., and Dolinsky, V.W. (2015). Sirtuin-3 (SIRT3) protein attenuates DOX-induced oxidative stress and improves mitochondrial respiration in H9c2 cardiomyocytes. J. Biol. Chem. 290, 10981–10993.10.1074/jbc.M114.607960Search in Google Scholar PubMed PubMed Central

Choudhary, C., Kumar, C., Gnad, F., Nielsen, M.L., Rehman, M., Walther, T.C., Olsen, J.V., and Mann, M. (2009). Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325, 834–840.10.1126/science.1175371Search in Google Scholar PubMed

Cimen, H., Han, M.J., Yang, Y., Tong, Q., Koc, H., and Koc, E.C. (2010). Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria. Biochemistry 49, 304–311.10.1021/bi901627uSearch in Google Scholar PubMed PubMed Central

Cini Neri, G., Neri, B., Bandinelli, M., Del Tacca, M., Danesi, R., and Riccardi, R. (1991). Anthracycline cardiotoxicity: in vivo and in vitro effects on biochemical parameters and heart ultrastructure of the rat. Oncology 48, 327–333.10.1159/000226952Search in Google Scholar PubMed

Daitoku, H., Hatta, M., Matsuzaki, H., Aratani, S., Ohshima, T., Miyagishi, M., Nakajima, T., and Fukamizu, A. (2004). Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc. Natl. Acad. Sci. USA 101, 10042–10047.10.1073/pnas.0400593101Search in Google Scholar PubMed PubMed Central

Danz, E.D., Skramsted, J., Henry, N., Bennett, J.A., and Keller, R.S. (2009). Resveratrol prevents DOX cardiotoxicity through mitochondrial stabilization and the Sirt1 pathway. Free Radic. Biol. Med. 46, 1589–1597.10.1016/j.freeradbiomed.2009.03.011Search in Google Scholar PubMed

de la Lastra, C.A. and Villegas, I. (2007). Resveratrol as an antioxidant and pro-oxidant agent: mechanisms and clinical implications. Biochem. Soc. Trans. 35, 1156–1160.10.1042/BST0351156Search in Google Scholar PubMed

Detmer, S.A. and Chan, D.C. (2007). Functions and dysfunctions of mitochondrial dynamics. Nat. Rev. Mol. Cell. Biol. 8, 870–879.10.1038/nrm2275Search in Google Scholar PubMed

Doenst, T., Pytel, G., Schrepper, A., Amorim, P., Farber, G., Shingu, Y., Mohr, F.W., and Schwarzer, M. (2010). Decreased rates of substrate oxidation ex vivo predict the onset of heart failure and contractile dysfunction in rats with pressure overload. Cardiovasc. Res. 86, 461–470.10.1093/cvr/cvp414Search in Google Scholar PubMed

Dolinsky, V.W. and Dyck, J.R. (2011). Calorie restriction and resveratrol in cardiovascular health and disease. Biochim. Biophys. Acta 1812, 1477–1489.10.1016/j.bbadis.2011.06.010Search in Google Scholar PubMed

Dolinsky, V.W., Rogan, K.J., Sung, M.M., Zordoky, B.N., Haykowsky, M.J., Young, M.E., Jones, L.W., and Dyck, J.R. (2013). Both aerobic exercise and resveratrol supplementation attenuate DOX-induced cardiac injury in mice. Am. J. Physiol. Endocrinol. Metab. 305, E243–E253.10.1152/ajpendo.00044.2013Search in Google Scholar PubMed PubMed Central

Doroshow, J.H. (1983). Effect of anthracycline antibiotics on oxygen radical formation in rat heart. Cancer Res. 43, 460–472.Search in Google Scholar

Du, J., Zhou, Y., Su, X., Yu, J.J., Khan, S., Jiang, H., Kim, J., Woo, J., Kim, J.H., Choi, B.H., and He, B. (2011). Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 334, 806–809.10.1126/science.1207861Search in Google Scholar PubMed PubMed Central

Dutta, D., Xu, J., Dirain, M.L., and Leeuwenburgh, C. (2014). Calorie restriction combined with resveratrol induces autophagy and protects 26-month-old rat hearts from doxorubicin-induced toxicity. Free Radic. Biol. Med. 74, 252–262.10.1016/j.freeradbiomed.2014.06.011Search in Google Scholar PubMed PubMed Central

Eidenschink, A.B., Schroter, G., Muller-Weihrich, S., and Stern, H. (2000). Myocardial high-energy phosphate metabolism is altered after treatment with anthracycline in childhood. Cardiol in the Young 10, 610–617.10.1017/S1047951100008891Search in Google Scholar

Ewer, M.S. and Ewer, S.M. (2010). Cardiotoxicity of anticancer treatments: what the cardiologist needs to know. Nat. Rev. Cardiol. 7, 564–575.10.1038/nrcardio.2010.121Search in Google Scholar PubMed

Finley, L.W., Carracedo, A., Lee, J., Souza, A., Egia, A., Zhang, J., Teruya-Feldstein, J., Moreira, P.I., Cardoso, S.M., Clish, C.B., et al. (2011). SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization. Cancer Cell 19, 416–428.10.1016/j.ccr.2011.02.014Search in Google Scholar PubMed PubMed Central

Furt, F. and Moreau, P. (2009). Importance of lipid metabolism for intracellular and mitochondrial membrane fusion/fission processes. Int. J. Biochem. Cell. Biol. 41, 1828–1836.10.1016/j.biocel.2009.02.005Search in Google Scholar PubMed

Gerhart-Hines, Z., Rodgers, J.T., Bare, O., Lerin, C., Kim, S.H., Mostoslavsky, R., Alt, F.W., Wu, Z., and Puigserver, P. (2007). Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J. 26, 1913–1923.10.1038/sj.emboj.7601633Search in Google Scholar PubMed PubMed Central

Gertz, M., Fischer, F., Nguyen, G.T., Lakshminarasimhan, M., Schutkowski, M., Weyand, M., and Steegborn, C. (2013). Ex-527 inhibits Sirtuins by exploiting their unique NAD+-dependent deacetylation mechanism. Proc. Natl. Acad. Sci. USA 110, E2772–E2781.10.1073/pnas.1303628110Search in Google Scholar PubMed PubMed Central

Grillon, J.M., Johnson, K.R., Kotlo, K., and Danziger, R.S. (2012). Non-histone lysine acetylated proteins in heart failure. Biochim. Biophys. Acta 1822, 607–614.10.1016/j.bbadis.2011.11.016Search in Google Scholar PubMed PubMed Central

Gupta, A., Akki, A., Wang, Y., Leppo, M.K., Chacko, V.P., Foster, D.B., Caceres, V., Shi, S., Kirk, J.A., Su, J., et al. (2012). Creatine kinase-mediated improvement of function in failing mouse hearts provides causal evidence the failing heart is energy starved. J. Clin. Invest. 122, 291–302.10.1172/JCI57426Search in Google Scholar PubMed PubMed Central

Gupta, A., Rohlfsen, C., Leppo, M.K., Chacko, V.P., Wang, Y., Steenbergen, C., and Weiss, R.G. (2013). Creatine kinase-overexpression improves myocardial energetics, contractile dysfunction and survival in murine DOX cardiotoxicity. PLoS One 8, e74675.10.1371/journal.pone.0074675Search in Google Scholar PubMed PubMed Central

Gurd, B.J., Yoshida, Y., McFarlan, J.T., Holloway, G.P., Moyes, C.D., Heigenhauser, G.J., Spriet, L., and Bonen, A. (2011). Nuclear SIRT1 activity, but not protein content, regulates mitochondrial biogenesis in rat and human skeletal muscle. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301, R67–R75.10.1152/ajpregu.00417.2010Search in Google Scholar PubMed

Hafner, A.V., Dai, J., Gomes, A.P., Xiao, C.Y., Palmeira, C.M., Rosenzweig, A., and Sinclair, D.A. (2010). Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. Aging 2, 914–923.10.18632/aging.100252Search in Google Scholar PubMed PubMed Central

Haigis, M.C., Deng, C.X., Finley, L.W., Kim, H.S., and Gius, D. (2012). SIRT3 is a mitochondrial tumor suppressor: a scientific tale that connects aberrant cellular ROS, the Warburg effect, and carcinogenesis. Cancer Res 72, 2468–2472.10.1158/0008-5472.CAN-11-3633Search in Google Scholar PubMed PubMed Central

Halaschek-Wiener, J., Amirabbasi-Beik, M., Monfared, N., Pieczyk, M., Sailer, C., Kollar, A., Thomas, R., Agalaridis, G., Yamada, S., Oliveira, L., et al. (2009). Genetic variation in healthy oldest-old. PLoS One 4, e6641.10.1371/journal.pone.0006641Search in Google Scholar PubMed PubMed Central

Hariharan, N., Maejima, Y., Nakae, J., Paik, J., Depinho, R.A., and Sadoshima, J. (2010). Deacetylation of FoxO by Sirt1 plays an essential role in mediating starvation-induced autophagy in cardiac myocytes. Circ. Res. 107, 1470–1482.10.1161/CIRCRESAHA.110.227371Search in Google Scholar PubMed PubMed Central

Hebert, A.S., Dittenhafer-Reed, K.E., Yu, W., Bailey, D.J., Selen, E.S., Boersma, M.D., Carson, J.J., Tonelli, M., Balloon, A.J., Higbee, A.J., et al. (2013). Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome. Mol. Cell 49, 186–199.10.1016/j.molcel.2012.10.024Search in Google Scholar PubMed PubMed Central

Hequet, O., Le, Q.H., Moullet, I., Pauli, E., Salles, G., Espinouse, D., Dumontet, C., Thieblemont, C., Arnaud, P., Antal, D., et al. (2004). Subclinical late cardiomyopathy after DOX therapy for lymphoma in adults. J. Clin. Oncol. 22, 1864–1871.10.1200/JCO.2004.06.033Search in Google Scholar PubMed

Hirschey, M.D., Shimazu, T., Goetzman, E., Jing, E., Schwer, B., Lombard, D.B., Grueter, C.A., Harris, C., Biddinger, S., Ilkayeva, O.R., et al. (2010). SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464, 121–125.10.1038/nature08778Search in Google Scholar PubMed PubMed Central

Hoshino, A., Mita, Y., Okawa, Y., Ariyoshi, M., Iwai-Kanai, E., Ueyama, T., Ikeda, K., Ogata, T., and Matoba, S. (2013). Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart. Nat. Commun. 4, 2308.10.1038/ncomms3308Search in Google Scholar PubMed

Howitz, K.T., Bitterman, K.J., Cohen, H.Y., Lamming, D.W., Lavu, S., Wood, J.G., Zipkin, R.E., Chung, P., Kisielewski, A., Zhang, L.L., et al. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191–196.10.1038/nature01960Search in Google Scholar

Hrelia, S., Fiorentini, D., Maraldi, T., Angeloni, C., Bordoni, A., Biagi, P.L., and Hakim, G. (2002). DOX induces early lipid peroxidation associated with changes in glucose transport in cultured cardiomyocytes. Biochim. Biophys. Acta 1567, 150–156.10.1016/S0005-2736(02)00612-0Search in Google Scholar

Hsu, C.P., Zhai, P., Yamamoto, T., Maejima, Y., Matsushima, S., Hariharan, N., Shao, D., Takagi, H., Oka, S., and Sadoshima, J. (2010). Silent information regulator 1 protects the heart from ischemia/reperfusion. Circulation 122, 2170–2182.10.1161/CIRCULATIONAHA.110.958033Search in Google Scholar PubMed PubMed Central

Huang, W.Y., Cai, Y.Z., Xing, J., Corke, H., and Sun, M. (2008). Comparative analysis of bioactivities of four Polygonum species. Planta Med. 74, 43–49.10.1055/s-2007-993759Search in Google Scholar PubMed

Hubbard, B.P., Gomes, A.P., Dai, H., Li, J., Case, A.W., Considine, T., Riera, T.V., Lee, J.E., Yen, S., Lamming, D.W., et al. (2013). Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science 339, 1216–1219.10.1126/science.1231097Search in Google Scholar PubMed PubMed Central

Ide, T., Tsutsui, H., Kinugawa, S., Utsumi, H., Kang, D., Hattori, N., Uchida, K., Arimura, K.I., Egashira, K., and Takeshita, A. (1999). Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circ. Res. 85, 357–363.10.1161/01.RES.85.4.357Search in Google Scholar

Inuzuka, H., Gao, D., Finley, L.W., Yang, W., Wan, L., Fukushima, H., Chin, Y.R., Zhai, B., Shaik, S., Lau, A.W., et al. (2012). Acetylation-dependent regulation of Skp2 function. Cell 150, 179–193.10.1016/j.cell.2012.05.038Search in Google Scholar PubMed PubMed Central

Iwahara, T., Bonasio, R., Narendra, V., and Reinberg, D. (2012). SIRT3 functions in the nucleus in the control of stress-related gene expression. Mol. Cell Biol. 32, 5022–5034.10.1128/MCB.00822-12Search in Google Scholar PubMed PubMed Central

Jatoi, I., Chen, B.E., Anderson, W.F., and Rosenberg, P.S. (2007). Breast cancer mortality trends in the United States according to estrogen receptor status and age at diagnosis. J. Clin. Oncol. 25, 1683–1690.10.1200/JCO.2006.09.2106Search in Google Scholar PubMed

Jeyaseelan, R., Poizat, C., Wu, H.Y., and Kedes, L. (1997). Molecular mechanisms of DOX-induced cardiomyopathy. Selective suppression of Reiske iron-sulfur protein, ADP/ATP translocase, and phosphofructokinase genes is associated with ATP depletion in rat cardiomyocytes. J. Biol. Chem. 272, 5828–5832.10.1074/jbc.272.9.5828Search in Google Scholar PubMed

Jin, S.M. and Youle, R.J. (2012). PINK1- and Parkin-mediated mitophagy at a glance. J. Cell Sci. 125, 795–799.10.1242/jcs.093849Search in Google Scholar PubMed PubMed Central

Jones, L.W., Haykowsky, M.J., Swartz, J.J., Douglas, P.S., and Mackey, J.R. (2007). Early breast cancer therapy and cardiovascular injury. J. Amer. Coll. Cardiol. 50, 1435–1441.10.1016/j.jacc.2007.06.037Search in Google Scholar PubMed

Jullig, M., Hickey, A.J., Chai, C.C., Skea, G.L., Middleditch, M.J., Costa, S., Choong, S.Y., Philips, A.R., and Cooper, G.J. (2008). Is the failing heart out of fuel or a worn engine running rich? A study of mitochondria in old spontaneously hypertensive rats. Proteomics 8, 2556–2572.10.1002/pmic.200700977Search in Google Scholar PubMed

Kanamori, H., Takemura, G., Goto, K., Tsujimoto, A., Ogino, A., Takeyama, T., Kawaguchi, T., Watanabe, T., Morishita, K., Kawasaki, M., et al. (2013). Resveratrol reverses remodeling in hearts with large, old myocardial infarctions through enhanced autophagy-activating AMP kinase pathway. Am. J. Pathol. 182, 701–713.10.1016/j.ajpath.2012.11.009Search in Google Scholar PubMed

Kang, P.T., Chen, C.L., Ohanyan, V., Luther, D.J., Meszaros, J.G., Chilian, W.M., and Chen, Y.R. (2015). Overexpressing superoxide dismutase 2 induces a supernormal cardiac function by enhancing redox-dependent mitochondrial function and metabolic dilation. J. Mol. Cell. Cardiol. 88, 14–28.10.1016/j.yjmcc.2015.09.001Search in Google Scholar PubMed PubMed Central

Karamanlidis, G., Lee, C.F., Garcia-Menendez, L., Kolwicz, S.C., Jr., Suthammarak, W., Gong, G., Sedensky, M.M., Morgan, P.G., Wang, W., and Tian, R. (2013). Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure. Cell Metab. 18, 239–250.10.1016/j.cmet.2013.07.002Search in Google Scholar PubMed PubMed Central

Kawaguchi, T., Takemura, G., Kanamori, H., Takeyama, T., Watanabe, T., Morishita, K., Ogino, A., Tsujimoto, A., Goto, K., Maruyama, R., et al. (2012). Prior starvation mitigates acute DOX cardiotoxicity through restoration of autophagy in affected cardiomyocytes. Cardiovasc. Res. 96, 456–465.10.1093/cvr/cvs282Search in Google Scholar PubMed

Kawamura, Y., Uchijima, Y., Horike, N., Tonami, K., Nishiyama, K., Amano, T., Asano, T., Kurihara, Y., and Kurihara, H. (2010). Sirt3 protects in vitro-fertilized mouse preimplantation embryos against oxidative stress-induced p53-mediated developmental arrest. J. Clin. Invest. 120, 2817–2828.10.1172/JCI42020Search in Google Scholar PubMed PubMed Central

Kendrick, A.A., Choudhury, M., Rahman, S.M., McCurdy, C.E., Friederich, M., Van Hove, J.L., Watson, P.A., Birdsey, N., Bao, J., Gius, D., et al. (2011). Fatty liver is associated with reduced SIRT3 activity and mitochondrial protein hyperacetylation. Biochem. J. 433, 505–514.10.1042/BJ20100791Search in Google Scholar PubMed PubMed Central

Kim, S.C., Sprung, R., Chen, Y., Xu, Y., Ball, H., Pei, J., Cheng, T., Kho, Y., Xiao, H., Xiao, L., et al. (2006). Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol. Cell 23, 607–618.10.1016/j.molcel.2006.06.026Search in Google Scholar PubMed

Kim, I., Rodriguez-Enriquez, S., and Lemasters, J.J. (2007). Selective degradation of mitochondria by mitophagy. Arch. Biochem. Biophys. 462, 245–253.10.1016/j.abb.2007.03.034Search in Google Scholar PubMed PubMed Central

Kim, H.S., Patel, K., Muldoon-Jacobs, K., Bisht, K.S., Aykin-Burns, N., Pennington, J.D., van der Meer, R., Nguyen, P., Savage, J., Owens, K.M., et al. (2010). SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 17, 41–52.10.1016/j.ccr.2009.11.023Search in Google Scholar PubMed PubMed Central

Kitagawa, K., Takeda, K., Saito, K., Okamoto, S., Makino, K., Maeda, H., and Ichihara, T. (2002). Differences in fatty acid metabolic disorder between ischemic myocardium and DOX-induced myocardial damage: assessment using BMIPP dynamic SPECT with analysis by the Rutland method. J. Nucl. Med. 43, 1286–1294.Search in Google Scholar

Koentges, C., Pfeil, K., Schnick, T., Wiese, S., Dahlbock, R., Cimolai, M.C., Meyer-Steenbuck, M., Cenkerova, K., Hoffmann, M.M., Jaeger, C., et al. (2015). SIRT3 deficiency impairs mitochondrial and contractile function in the heart. Basic Res. Cardiol. 110, 36.10.1007/s00395-015-0493-6Search in Google Scholar PubMed

Kong, X., Wang, R., Xue, Y., Liu, X., Zhang, H., Chen, Y., Fang, F., and Chang, Y. (2010). Sirtuin 3, a new target of PGC-1alpha, plays an important role in the suppression of ROS and mitochondrial biogenesis. PLoS One 5, e11707.10.1371/journal.pone.0011707Search in Google Scholar PubMed PubMed Central

Kotamraju, S., Konorev, E.A., Joseph, J., and Kalyanaraman, B. (2000). DOX-induced apoptosis in endothelial cells and cardiomyocytes is ameliorated by nitrone spin traps and ebselen. Role of reactive oxygen and nitrogen species. J. Biol. Chem. 275, 33585–33592.10.1074/jbc.M003890200Search in Google Scholar PubMed

Ladas, E.J., Jacobson, J.S., Kennedy, D.D., Teel, K., Fleischauer, A., and Kelly, K.M. (2004). Antioxidants and cancer therapy: a systematic review. J. Clin. Oncol. 22, 517–528.10.1200/JCO.2004.03.086Search in Google Scholar PubMed

Lagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H., Lerin, C., Daussin, F., Messadeq, N., Milne, J., Lambert, P., Elliott, P., et al. (2006). Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 1109–1122.10.1016/j.cell.2006.11.013Search in Google Scholar PubMed

Lai, Y.C., Tabima, D.M., Dube, J.J., Hughan, K.S., Vanderpool, R.R., Goncharov, D.A., Croix, C.M.S., Garcia-Ocaña, A., Goncharova, E.A., Tofovic, S.P., et al. (2016). SIRT3-AMP-activated protein kinase activation by nitrite and metformin improves hyperglycemia and normalizes pulmonary hypertension associated with heart failure with preserved ejection fraction. Circulation 133, 717–731.10.1161/CIRCULATIONAHA.115.018935Search in Google Scholar PubMed PubMed Central

Lambert, A.J. and Brand, M.D. (2007). Research on mitochondria and aging, 2006–2007. Aging Cell 6, 417–420.10.1111/j.1474-9726.2007.00316.xSearch in Google Scholar PubMed

Lambert, A.J. and Brand, M.D. (2009). ROS production by mitochondria. Methods Mol. Biol. 554, 165–181.10.1007/978-1-59745-521-3_11Search in Google Scholar PubMed

Lee, I.H., Cao, L., Mostoslavsky, R., Lombard, D.B., Liu, J., Bruns, N.E., Tsokos, M., Alt, F.W., and Finkel, T. (2008). A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc. Natl. Acad. Sci. USA 105, 3374–3379.10.1073/pnas.0712145105Search in Google Scholar

Lescai, F., Blanche, H., Nebel, A., Beekman, M., Sahbatou, M., Flachsbart, F., Slagboom, E., Schreiber, S., Sorbi, S., Passarino, G., et al. (2009). Human longevity and 11p15.5: a study in 1321 centenarians. Eur. J. Hum. Genet. 17, 1515–1519.10.1038/ejhg.2009.54Search in Google Scholar

Li, Y., Huang, T.T., Carlson, E.J., Melov, S., Ursell, P.C., Olson, J.L., Noble, L.J., Yoshimura, M.P., Berger, C., Chan, P.H., et al. (1995). Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat. Genet. 11, 376–381.10.1038/ng1295-376Search in Google Scholar

Li, D.L., Wang, Z.V., Ding, G., Tan, W., Luo, X., Criollo, A., Xie, M., Jiang, N., May, H., Kyrychenko, V., et al. (2016). DOX blocks cardiomyocyte autophagic flux by inhibiting lysosome acidification. Circulation 133, 1668–1687.10.1161/CIRCULATIONAHA.115.017443Search in Google Scholar

Liu, M.H., Shan, J., Li, J., Zhang, Y., and Lin, X.L. (2016). Resveratrol inhibits DOX-induced cardiotoxicity via sirtuin 1 activation in H9c2 cardiomyocytes. Exp. Ther. Med. 12, 1113–1118.10.3892/etm.2016.3437Search in Google Scholar

Lombard, D.B., Alt, F.W., Cheng, H.L., Bunkenborg, J., Streeper, R.S., Mostoslavsky, R., Kim, J., Yancopoulos, G., Valenzuela, D., Murphy, A., et al. (2007). Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol. Cell Biol. 27, 8807–8814.10.1128/MCB.01636-07Search in Google Scholar

Lopaschuk, G.D., Belke, D.D., Gamble, J., Itoi, T., and Schonekess, B.O. (1994). Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim. Biophys. Acta 1213, 263–276.10.1016/0005-2760(94)00082-4Search in Google Scholar

Lou, Y., Wang, Z., Xu, Y., Zhou, P., Cao, J., Li, Y., Chen, Y., Sun, J., and Fu, L. (2015). Resveratrol prevents DOX-induced cardiotoxicity in H9c2 cells through the inhibition of endoplasmic reticulum stress and the activation of the Sirt1 pathway. Int. J. Mol. Med. 36, 873–880.10.3892/ijmm.2015.2291Search in Google Scholar PubMed

Lu, L., Wu, W., Yan, J., Li, X., Yu, H., and Yu, X. (2009). Adriamycin-induced autophagic cardiomyocyte death plays a pathogenic role in a rat model of heart failure. Int. J. Cardiol. 134, 82–90.10.1016/j.ijcard.2008.01.043Search in Google Scholar PubMed

Lu, T.M., Tsai, J.Y., Chen, Y.C., Huang, C.Y., Hsu, H.L., Weng, C.F., Shih, C.C., and Hsu, C.P. (2014). Downregulation of Sirt1 as aging change in advanced heart failure. J. Biomed. Sci. 21, 57.10.1186/1423-0127-21-57Search in Google Scholar PubMed PubMed Central

Lu, Z., Chen, Y., Aponte, A.M., Battaglia, V., Gucek, M., and Sack, M.N. (2015). Prolonged fasting identifies heat shock protein 10 as a Sirtuin 3 substrate: elucidating a new mechanism linking mitochondrial protein acetylation to fatty acid oxidation enzyme folding and function. J. Biol. Chem. 290, 2466–2476.10.1074/jbc.M114.606228Search in Google Scholar

Marques-Aleixo, I., Santos-Alves, E., Mariani, D., Rizo-Roca, D., Padrao, A.I., Rocha-Rodrigues, S., Viscor, G., Torrella, J.R., Ferreira, R., Oliveira, P.J., et al. (2014). Physical exercise prior and during treatment reduces sub-chronic DOX-induced mitochondrial toxicity and oxidative stress. Mitochondrion 20C, 22–33.Search in Google Scholar

Masoud, W.G., Ussher, J.R., Wang, W., Jaswal, J.S., Wagg, C.S., Dyck, J.R., Lygate, C.A., Neubauer, S., Clanachan, A.S., and Lopaschuk, G.D. (2014). Failing mouse hearts utilize energy inefficiently and benefit from improved coupling of glycolysis and glucose oxidation. Cardiovasc. Res. 101, 30–38.10.1093/cvr/cvt216Search in Google Scholar

McMurray, J.J. and Pfeffer, M.A. (2005). Heart failure. Lancet 365, 1877–1889.10.1016/S0140-6736(05)66621-4Search in Google Scholar

Menna, P., Recalcati, S., Cairo, G., and Minotti, G. (2007). An introduction to the metabolic determinants of anthracycline cardiotoxicity. Cardiovasc. Toxicol. 7, 80–85.10.1007/s12012-007-0011-7Search in Google Scholar

Mihm, M.J., Yu, F., Weinstein, D.M., Reiser, P.J., and Bauer, J.A. (2002). Intracellular distribution of peroxynitrite during DOX cardiomyopathy: evidence for selective impairment of myofibrillar creatine kinase. Br. J. Pharmacol. 135, 581–588.10.1038/sj.bjp.0704495Search in Google Scholar

Monti, E., Prosperi, E., Supino, R., and Bottiroli, G. (1995). Free radical-dependent DNA lesions are involved in the delayed cardiotoxicity induced by adriamycin in the rat. Anticancer Res. 15, 193–197.Search in Google Scholar

Moulin, M., Piquereau, J., Mateo, P., Fortin, D., Rucker-Martin, C., Gressette, M., Lefebvre, F., Gresikova, M., Solgadi, A., Veksler, V., et al. (2015a). Sexual dimorphism of DOX-mediated cardiotoxicity: potential role of energy metabolism remodeling. Circ. Heart Fail. 8, 98–108.10.1161/CIRCHEARTFAILURE.114.001180Search in Google Scholar

Moulin, M., Solgadi, A., Veksler, V., Garnier, A., Ventura-Clapier, R., and Chaminade, P. (2015b). Sex-specific cardiac cardiolipin remodelling after DOX treatment. Biol. Sex Differ. 6, 20.10.1186/s13293-015-0039-5Search in Google Scholar

Muhammed, H., Ramasarma, T., and Kurup, C.K. (1983). Inhibition of mitochondrial oxidative phosphorylation by adriamycin. Biochim. Biophys. Acta 722, 43–50.10.1016/0005-2728(83)90155-XSearch in Google Scholar

Murray, A.J., Cole, M.A., Lygate, C.A., Carr, C.A., Stuckey, D.J., Little, S.E., Neubauer, S., and Clarke, K. (2008). Increased mitochondrial uncoupling proteins, respiratory uncoupling and decreased efficiency in the chronically infarcted rat heart. J. Mol. Cell. Cardiol. 44, 694–700.10.1016/j.yjmcc.2008.01.008Search in Google Scholar PubMed

Nakai, A., Yamaguchi, O., Takeda, T., Higuchi, Y., Hikoso, S., Taniike, M., Omiya, S., Mizote, I., Matsumura, Y., Asahi, M., et al. (2007). The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat. Med. 13, 619–624.10.1038/nm1574Search in Google Scholar PubMed

Nakamura, K., Kusano, K.F., Matsubara, H., Nakamura, Y., Miura, A., Nishii, N., Banba, K., Nagase, S., Miyaji, K., Morita, H., et al. (2005). Relationship between oxidative stress and systolic dysfunction in patients with hypertrophic cardiomyopathy. J. Card. Fail. 11, 117–123.10.1016/j.cardfail.2004.05.005Search in Google Scholar

Neubauer, S., Krahe, T., Schindler, R., Horn, M., Hillenbrand, H., Entzeroth, C., Mader, H., Kromer, E.P., Riegger, G.A., and Lackner, K. (1992). 31P magnetic resonance spectroscopy in dilated cardiomyopathy and coronary artery disease. Altered cardiac high-energy phosphate metabolism in heart failure. Circulation 86, 1810–1818.10.1161/01.CIR.86.6.1810Search in Google Scholar

Neubauer, S., Horn, M., Pabst, T., Godde, M., Lubke, D., Jilling, B., Hahn, D., and Ertl, G. (1995). Contributions of 31P-magnetic resonance spectroscopy to the understanding of dilated heart muscle disease. Eur. Heart J. 16, 115–118.10.1093/eurheartj/16.suppl_O.115Search in Google Scholar

Nicolay, K. and de Kruijff, B. (1987). Effects of adriamycin on respiratory chain activities in mitochondria from rat liver, rat heart and bovine heart. Evidence for a preferential inhibition of complex III and IV. Biochim. Biophys. Acta 892, 320–330.10.1016/0005-2728(87)90236-2Search in Google Scholar

Nicolay, K., Aue, W.P., Seelig, J., van Echteld, C.J., Ruigrok, T.J., and de Kruijff, B. (1987). Effects of the anti-cancer drug adriamycin on the energy metabolism of rat heart as measured by in vivo31P-NMR and implications for adriamycin-induced cardiotoxicity. Biochim. Biophys. Acta 929, 5–13.10.1016/0167-4889(87)90234-5Search in Google Scholar

Nojiri, H., Shimizu, T., Funakoshi, M., Yamaguchi, O., Zhou, H., Kawakami, S., Ohta, Y., Sami, M., Tachibana, T., Ishikawa, H., et al. (2006). Oxidative stress causes heart failure with impaired mitochondrial respiration. J. Biol. Chem. 281, 33789–33801.10.1074/jbc.M602118200Search in Google Scholar PubMed

Nysom, K., Holm, K., Lipsitz, S.R., Mone, S.M., Colan, S.D., Orav, E.J., Sallan, S.E., Olsen, J.H., Hertz, H., Jacobsen, J.R., et al. (1998). Relationship between cumulative anthracycline dose and late cardiotoxicity in childhood acute lymphoblastic leukemia. J. Clin. Oncol. 16, 545–550.10.1200/JCO.1998.16.2.545Search in Google Scholar PubMed

Obrzut, S., Tiongson, J., Jamshidi, N., Phan, H.M., Hoh, C., and Birgersdotter-Green, U. (2010). Assessment of metabolic phenotypes in patients with non-ischemic dilated cardiomyopathy undergoing cardiac resynchronization therapy. J. Cardiovasc. Transl. Res. 3, 643–651.10.1007/s12265-010-9223-5Search in Google Scholar PubMed PubMed Central

Oka, S., Alcendor, R., Zhai, P., Park, J.Y., Shao, D., Cho, J., Yamamoto, T., Tian, B., and Sadoshima, J. (2011). PPARalpha-Sirt1 complex mediates cardiac hypertrophy and failure through suppression of the ERR transcriptional pathway. Cell Metab. 14, 598–611.10.1016/j.cmet.2011.10.001Search in Google Scholar PubMed PubMed Central

Olson, R.D., MacDonald, J.S., vanBoxtel, C.J., Boerth, R.C., Harbison, R.D., Slonim, A.E., Freeman, R.W., and Oates, J.A. (1980). Regulatory role of glutathione and soluble sulfhydryl groups in the toxicity of adriamycin. J. Pharmacol. Exper. Therap. 215, 450–454.Search in Google Scholar

Patnaik, J.L., Byers, T., DiGuiseppi, C., Dabelea, D., and Denberg, T.D. (2011). Cardiovascular disease competes with breast cancer as the leading cause of death for older females diagnosed with breast cancer: a retrospective cohort study. Breast Cancer Res. 13, R64.10.1186/bcr2901Search in Google Scholar PubMed PubMed Central

Pelikan, P.C., Weisfeldt, M.L., Jacobus, W.E., Miceli, M.V., Bulkley, B.H., and Gerstenblith, G. (1986). Acute DOX cardiotoxicity: functional, metabolic, and morphologic alterations in the isolated, perfused rat heart. J. Cardiovasc. Pharmacol. 8, 1058–1066.10.1097/00005344-198609000-00026Search in Google Scholar

Perez, E.A., Suman, V.J., Davidson, N.E., Kaufman, P.A., Martino, S., Dakhil, S.R., Ingle, J.N., Rodeheffer, R.J., Gersh, B.J., and Jaffe, A.S. (2004). Effect of DOX plus cyclophosphamide on left ventricular ejection fraction in patients with breast cancer in the North Central Cancer Treatment Group N9831 Intergroup Adjuvant Trial. J. Clin. Oncol. 22, 3700–3704.10.1200/JCO.2004.03.516Search in Google Scholar PubMed

Perez, E.A., Suman, V.J., Davidson, N.E., Sledge, G.W., Kaufman, P.A., Hudis, C.A., Martino, S., Gralow, J.R., Dakhil, S.R., Ingle, J.N., et al. (2008). Cardiac safety analysis of DOX and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial. J. Clin. Oncol. 26, 1231–1238.10.1200/JCO.2007.13.5467Search in Google Scholar PubMed PubMed Central

Pillai, V.B., Sundaresan, N.R., Kim, G., Gupta, M., Rajamohan, S.B., Pillai, J.B., Samant, S., Ravindra, P.V., Isbatan, A., and Gupta, M.P. (2010). Exogenous NAD blocks cardiac hypertrophic response via activation of the SIRT3-LKB1-AMPK pathway. J. Biol. Chem. 285, 3133–3144.10.1074/jbc.M109.077271Search in Google Scholar PubMed PubMed Central

Pillai, V.B., Samant, S., Sundaresan, N.R., Raghuraman, H., Kim, G., Bonner, M.Y., Arbiser, J.L., Walker, D.I., Jones, D.P., Gius, D., et al. (2015). Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3. Nat. Commun. 6, 6656.10.1038/ncomms7656Search in Google Scholar PubMed PubMed Central

Pillai, V.B., Bindu, S., Sharp, W., Fang, Y.H., Kim, G., Gupta, M., Samant, S., and Gupta, M.P. (2016). Sirt3 protects mitochondrial DNA damage and blocks the development of DOX-induced cardiomyopathy in mice. Am. J. Physiol. Heart Circ. Physiol. 310, H962–H972.10.1152/ajpheart.00832.2015Search in Google Scholar PubMed PubMed Central

Pinder, M.C., Duan, Z., Goodwin, J.S., Hortobagyi, G.N., and Giordano, S.H. (2007). Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer. J. Clin. Oncol. 25, 3808–3815.10.1200/JCO.2006.10.4976Search in Google Scholar PubMed

Pizarro, M., Troncoso, R., Martinez, G.J., Chiong, M., Castro, P.F., and Lavandero, S. (2016). Basal autophagy protects cardiomyocytes from DOX-induced toxicity. Toxicology 370, 41–48.10.1016/j.tox.2016.09.011Search in Google Scholar PubMed

Planavila, A., Dominguez, E., Navarro, M., Vinciguerra, M., Iglesias, R., Giralt, M., Lope-Piedrafita, S., Ruberte, J., and Villarroya, F. (2012). Dilated cardiomyopathy and mitochondrial dysfunction in Sirt1-deficient mice: a role for Sirt1-Mef2 in adult heart. J. Mol. Cell Cardiol. 53, 521–531.10.1016/j.yjmcc.2012.07.019Search in Google Scholar PubMed

Pointon, A.V., Walker, T.M., Phillips, K.M., Luo, J., Riley, J., Zhang, S.D., Parry, J.D., Lyon, J.J., Marczylo, E.L., and Gant, T.W. (2010). DOX in vivo rapidly alters expression and translation of myocardial electron transport chain genes, leads to ATP loss and caspase 3 activation. PLoS One 5, e12733.10.1371/journal.pone.0012733Search in Google Scholar PubMed PubMed Central

Porter, G.A., Urciuoli, W.R., Brookes, P.S., and Nadtochiy, S.M. (2014). SIRT3 deficiency exacerbates ischemia-reperfusion injury: implication for aged hearts. Am. J. Physiol. Heart Circ. Physiol. 306, H1602–H1609.10.1152/ajpheart.00027.2014Search in Google Scholar PubMed PubMed Central

Qiu, X., Brown, K., Hirschey, M.D., Verdin, E., and Chen, D. (2010). Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab. 12, 662–667.10.1016/j.cmet.2010.11.015Search in Google Scholar PubMed

Rahman, M., Nirala, N.K., Singh, A., Zhu, L.J., Taguchi, K., Bamba, T., Fukusaki, E., Shaw, L.M., Lambright, D.G., Acharya, J.K., et al. (2014). Drosophila Sirt2/mammalian SIRT3 deacetylates ATP synthase β and regulates complex V activity. J. Cell Biol. 206, 289–305.10.1083/jcb.201404118Search in Google Scholar PubMed PubMed Central

Rardin, M.J., Newman, J.C., Held, J.M., Cusack, M.P., Sorensen, D.J., Li, B., Schilling, B., Mooney, S.D., Kahn, C.R., Verdin, E., et al. (2013). Label-free quantitative proteomics of the lysine acetylome in mitochondria identifies substrates of SIRT3 in metabolic pathways. Proc. Natl. Acad. Sci. USA 110, 6601–6606.10.1073/pnas.1302961110Search in Google Scholar PubMed PubMed Central

Ruan, Y., Dong, C., Patel, J., Duan, C., Wang, X., Wu, X., Cao, Y., Pu, L., Lu, D., Shen, T., et al. (2015). SIRT1 suppresses DOX-induced cardiotoxicity by regulating the oxidative stress and p38MAPK pathways. Cell Physiol. Biochem. 35, 1116–1124.10.1159/000373937Search in Google Scholar PubMed

Sack, M.N., Rader, T.A., Park, S., Bastin, J., McCune, S.A., and Kelly, D.P. (1996). Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation 94, 2837–2842.10.1161/01.CIR.94.11.2837Search in Google Scholar PubMed

Samant, S.A., Zhang, H.J., Hong, Z., Pillai, V.B., Sundaresan, N.R., Wolfgeher, D., Archer, S.L., Chan, D.C., and Gupta, M.P. (2014). SIRT3 deacetylates and activates OPA1 to regulate mitochondrial dynamics during stress. Mol. Cell Biol. 34, 807–819.10.1128/MCB.01483-13Search in Google Scholar PubMed PubMed Central

Sayed-Ahmed, M.M., Shouman, S.A., Rezk, B.M., Khalifa, M.H., Osman, A.M., and El-Merzabani, M.M. (2000). Propionyl-L-carnitine as potential protective agent against adriamycin-induced impairment of fatty acid beta-oxidation in isolated heart mitochondria. Pharmacol. Res. 41, 143–150.10.1006/phrs.1999.0583Search in Google Scholar PubMed

Schwer, B. and Verdin, E. (2008). Conserved metabolic regulatory functions of sirtuins. Cell Metab. 7, 104–112.10.1016/j.cmet.2007.11.006Search in Google Scholar PubMed

Schwer, B., Bunkenborg, J., Verdin, R.O., Andersen, J.S., and Verdin, E. (2006). Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc. Natl. Acad. Sci. USA 103, 10224–10229.10.1073/pnas.0603968103Search in Google Scholar PubMed PubMed Central

Seddon, M., Looi, Y.H., and Shah, A.M. (2007). Oxidative stress and redox signalling in cardiac hypertrophy and heart failure. Heart 93, 903–907.10.1136/hrt.2005.068270Search in Google Scholar

Seraydarian, M.W., Artaza, L., and Goodman, M.F. (1977). Adriamycin: effect on mammalian cardiac cells in culture. I. Cell population and energy metabolism. J. Mol. Cell Cardiol. 9, 375–382.10.1016/S0022-2828(77)80004-7Search in Google Scholar

Shneyvays, V., Mamedova, L., Zinman, T., Jacobson, K., and Shainberg, A. (2001). Activation of A (3)adenosine receptor protects against DOX-induced cardiotoxicity. J. Mol. Cell Cardiol. 33, 1249–1261.10.1006/jmcc.2001.1387Search in Google Scholar PubMed

Signorelli, P. and Ghidoni, R. (2005). Resveratrol as an anticancer nutrient: molecular basis, open questions and promises. J. Nutr. Biochem. 16, 449–466.10.1016/j.jnutbio.2005.01.017Search in Google Scholar PubMed

Sin, T.K., Yu, A.P., Yung, B.Y., Yip, S.P., Chan, L.W., Wong, C.S., Ying, M., Rudd, J.A., and Siu, P.M. (2014). Modulating effect of SIRT1 activation induced by resveratrol on Foxo1-associated apoptotic signalling in senescent heart. J. Physiol. 592, 2535–2548.10.1113/jphysiol.2014.271387Search in Google Scholar PubMed PubMed Central

Sin, T.K., Tam, B.T., Yung, B.Y., Yip, S.P., Chan, L.W., Wong, C.S., Ying, M., Rudd, J.A., and Siu, P.M. (2015). Resveratrol protects against DOX-induced cardiotoxicity in aged hearts through the SIRT1-USP7 axis. J. Physiol. 593, 1887–1899.10.1113/jphysiol.2014.270101Search in Google Scholar PubMed PubMed Central

Singal, P.K. and Panagia, V. (1984). Direct effects of adriamycin on the rat heart sarcolemma. Res. Comm. Chem. Pathol. Pharmacol. 43, 67–77.Search in Google Scholar

Sishi, B.J., Loos, B., van Rooyen, J., and Engelbrecht, A.M. (2013). Autophagy upregulation promotes survival and attenuates DOX-induced cardiotoxicity. Biochem. Pharmacol. 85, 124–134.10.1016/j.bcp.2012.10.005Search in Google Scholar PubMed

Smuder, A.J., Kavazis, A.N., Min, K., and Powers, S.K. (2013). DOX-induced markers of myocardial autophagic signaling in sedentary and exercise trained animals. J. Appl. Physiol. 115, 176–185.10.1152/japplphysiol.00924.2012Search in Google Scholar PubMed

Sol, E.M., Wagner, S.A., Weinert, B.T., Kumar, A., Kim, H.S., Deng, C.X., and Choudhary, C. (2012). Proteomic investigations of lysine acetylation identify diverse substrates of mitochondrial deacetylase sirt3. PLoS One 7, e50545.10.1371/journal.pone.0050545Search in Google Scholar PubMed PubMed Central

Stanley, W.C., Recchia, F.A., and Lopaschuk, G.D. (2005). Myocardial substrate metabolism in the normal and failing heart. Physiol. Rev. 85, 1093–1129.10.1152/physrev.00006.2004Search in Google Scholar PubMed

Sun, T., Li, X., Zhang, P., Chen, W.D., Zhang, H.L., Li, D.D., Deng, R., Qian, X.J., Jiao, L., Ji, J., et al. (2015). Acetylation of Beclin 1 inhibits autophagosome maturation and promotes tumour growth. Nat. Commun. 6, 7215.10.1038/ncomms8215Search in Google Scholar PubMed PubMed Central

Sundaresan, N.R., Samant, S.A., Pillai, V.B., Rajamohan, S.B., and Gupta, M.P. (2008). SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70. Mol. Cell Biol. 28, 6384–6401.10.1128/MCB.00426-08Search in Google Scholar PubMed PubMed Central

Sundaresan, N.R., Gupta, M., Kim, G., Rajamohan, S.B., Isbatan, A., and Gupta, M.P. (2009). Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J. Clin. Invest. 119, 2758–2771.10.1172/JCI39162Search in Google Scholar PubMed PubMed Central

Sundaresan, N.R., Bindu, S., Pillai, V.B., Samant, S., Pan, Y., Huang, J.Y., Gupta, M., Nagalingam, R.S., Wolfgeher, D., Verdin, E., et al. (2016). SIRT3 blocks aging-associated tissue fibrosis in mice by deacetylating and activating glycogen synthase kinase 3β. Mol. Cell Biol. 36, 678–692.10.1128/MCB.00586-15Search in Google Scholar PubMed PubMed Central

Swain, S.M., Whaley, F.S., and Ewer, M.S. (2003). Congestive heart failure in patients treated with DOX: a retrospective analysis of three trials. Cancer 97, 2869–2879.10.1002/cncr.11407Search in Google Scholar PubMed

Taegtmeyer, H. (2000). Genetics of energetics: transcriptional responses in cardiac metabolism. Ann. Biomed. Eng. 28, 871–876.10.1114/1.1312187Search in Google Scholar PubMed

Taegtmeyer, H. (2004). Cardiac metabolism as a target for the treatment of heart failure. Circulation 110, 894–896.10.1161/01.CIR.0000139340.88769.D5Search in Google Scholar PubMed

Tan-Chiu, E., Yothers, G., Romond, E., Geyer, C.E., Ewer, M., Keefe, D., Shannon, R.P., Swain, S.M., Brown, A., Fehrenbacher, L., et al. (2005). Assessment of cardiac dysfunction in a randomized trial comparing DOX and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J. Clin. Oncol. 23, 7811–7819.10.1200/JCO.2005.02.4091Search in Google Scholar PubMed

Taneike, M., Yamaguchi, O., Nakai, A., Hikoso, S., Takeda, T., Mizote, I., Oka, T., Tamai, T., Oyabu, J., Murakawa, T., et al. (2010). Inhibition of autophagy in the heart induces age-related cardiomyopathy. Autophagy 6, 600–606.10.4161/auto.6.5.11947Search in Google Scholar PubMed

Tanno, M., Sakamoto, J., Miura, T., Shimamoto, K., and Horio, Y. (2007). Nucleocytoplasmic shuttling of the NAD+-dependent histone deacetylase SIRT1. J. Biol. Chem. 282, 6823–6832.10.1074/jbc.M609554200Search in Google Scholar PubMed

Tanno, M., Kuno, A., Yano, T., Miura, T., Hisahara, S., Ishikawa, S., Shimamoto, K., and Horio, Y. (2010). Induction of manganese superoxide dismutase by nuclear translocation and activation of SIRT1 promotes cell survival in chronic heart failure. J. Biol. Chem. 285, 8375–8382.10.1074/jbc.M109.090266Search in Google Scholar PubMed PubMed Central

Tao, R., Coleman, M.C., Pennington, J.D., Ozden, O., Park, S.H., Jiang, H., Kim, H.S., Flynn, C.R., Hill, S., McDonald, W.H., et al. (2010). Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol. Cell 40, 893–904.10.1016/j.molcel.2010.12.013Search in Google Scholar PubMed PubMed Central

Tong, J., Ganguly, P.K., and Singal, P.K. (1991). Myocardial adrenergic changes at two stages of heart failure due to adriamycin treatment in rats. Am. J. Physiol. 260, H909–H916.10.1152/ajpheart.1991.260.3.H909Search in Google Scholar PubMed

Urbonavicius, S., Wiggers, H., Botker, H.E., Nielsen, T.T., Kimose, H.H., Østergaard, M., Lindholt, J.S., Vorum, H., and Honoré, B. (2009). Proteomic analysis identifies mitochondrial metabolic enzymes as major discriminators between different stages of the failing human myocardium. Acta Cardiol. 64, 511–522.10.2143/AC.64.4.2041617Search in Google Scholar PubMed

van Dalen, E.C., Caron, H.N., Dickinson, H.O., and Kremer, L.C. (2005). Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane database of systematic reviews (online): CD003917.Search in Google Scholar

Vassilopoulos, A., Pennington, J.D., Andresson, T., Rees, D.M., Bosley, A.D., Fearnley, I.M., Ham, A., Flynn, C.R., Hill, S., Rose, K.L., et al. (2014). SIRT3 deacetylates ATP synthase F1 complex proteins in response to nutrient- and exercise-induced stress. Antioxid. Redox Signal 21, 551–564.10.1089/ars.2013.5420Search in Google Scholar PubMed PubMed Central

Vinciguerra, M., Santini, M.P., Claycomb, W.C., Ladurner, A.G., and Rosenthal, N. (2010). Local IGF-1 isoform protects cardiomyocytes from hypertrophic and oxidative stresses via SirT1 activity. Aging 2, 43–62.10.18632/aging.100107Search in Google Scholar PubMed PubMed Central

Von Hoff, D.D., Layard, M.W., Basa, P., Davis, H.L., Von Hoff, A.L., Rozencweig, M., and Muggia, F.M. (1979). Risk factors for DOX-induced congestive heart failure. Ann. Intern. Med. 91, 710–717.10.7326/0003-4819-91-5-710Search in Google Scholar PubMed

Wang, B., Yang, Q., Sun, Y.Y., Xing, Y.F., Wang, Y.B., Lu, X.T., Bai, W.W., Liu, X.Q., and Zhao, Y.X. (2014). Resveratrol-enhanced autophagic flux ameliorates myocardial oxidative stress injury in diabetic mice. J. Cell Mol. Med. 18, 1599–1611.10.1111/jcmm.12312Search in Google Scholar PubMed PubMed Central

Weber, T.A. and Reichert, A.S. (2010). Impaired quality control of mitochondria: aging from a new perspective. Exp. Gerontol. 45, 503–511.10.1016/j.exger.2010.03.018Search in Google Scholar PubMed

Webster, B.R., Scott, I., Han, K., Li, J.H., Lu, Z., Stevens, M.V., Malide, D., Chen, Y., Samsel, L., Connelly, P.S., et al. (2013). Restricted mitochondrial protein acetylation initiates mitochondrial autophagy. J. Cell Sci. 126, 4843–4849.10.1242/jcs.131300Search in Google Scholar PubMed PubMed Central

Yang, Y., Hubbard, B.P., Sinclair, D.A., and Tong, Q. (2010). Characterization of murine SIRT3 transcript variants and corresponding protein products. J. Cell Biochem. 111, 1051–1058.10.1002/jcb.22795Search in Google Scholar PubMed PubMed Central

Yen, H.C., Oberley, T.D., Gairola, C.G., Szweda, L.I., and St Clair, D.K. (1999). Manganese superoxide dismutase protects mitochondrial complex I against adriamycin-induced cardiomyopathy in transgenic mice. Arch. Biochem. Biophys. 362, 59–66.10.1006/abbi.1998.1011Search in Google Scholar PubMed

Yu, J. and Auwerx, J. (2009). The role of sirtuins in the control of metabolic homeostasis. Ann. NY Acad. Sci. 1173, E10–E19.10.1111/j.1749-6632.2009.04952.xSearch in Google Scholar PubMed PubMed Central

Yu, W., Dittenhafer-Reed, K.E., and Denu, J.M. (2012). SIRT3 protein deacetylates isocitrate dehydrogenase 2 and regulates mitochondrial redox status. J. Biol. Chem. 287, 14078–14086.10.1074/jbc.M112.355206Search in Google Scholar PubMed PubMed Central

Yu, W., Gao, B., Li, N., Wang, J., Qiu, C., Zhang, G., Liu, M., Zhang, R., Li, C., Ji, G., et al. (2016). Sirt3 deficiency exacerbates diabetic cardiac dysfunction: role of Foxo3A-Parkin-mediated mitophagy. Biochim. Biophys. Acta. doi: 10.1016/j.bbadis.2016.10.021.10.1016/j.bbadis.2016.10.021Search in Google Scholar PubMed

Yue, Z., Ma, Y., You, J., Li, Z., Ding, Y., He, P., Lu, X., Jiang, J., Chen, S., and Liu, P. (2016). NMNAT3 is involved in the protective effect of SIRT3 in Ang II-induced cardiac hypertrophy. Exp. Cell Res. 347, 261–273.10.1016/j.yexcr.2016.07.006Search in Google Scholar PubMed

Zhang, Y.W., Shi, J., Li, Y.J., and Wei, L. (2009). Cardiomyocyte death in DOX-induced cardiotoxicity. Arch. Immunol. Ther. Exp. 57, 435–445.10.1007/s00005-009-0051-8Search in Google Scholar PubMed PubMed Central

Zhang, C., Feng, Y., Qu, S., Wei, X., Zhu, H., Luo, Q., Liu, M., Chen, G., and Xiao, X. (2011). Resveratrol attenuates DOX-induced cardiomyocyte apoptosis in mice through SIRT1-mediated deacetylation of p53. Cardiovasc Res. 90, 538–545.10.1093/cvr/cvr022Search in Google Scholar PubMed

Zhang, C.Z., Liu, L., Cai, M., Pan, Y., Fu, J., Cao, Y., and Yun, J. (2012). Low SIRT3 expression correlates with poor differentiation and unfavorable prognosis in primary hepatocellular carcinoma. PLoS One 7, e51703.10.1371/journal.pone.0051703Search in Google Scholar PubMed PubMed Central

Zhang, Y., Bharathi, S.S., Rardin, M.J., Uppala, R., Verdin, E., Gibson, B.W., and Goetzman, E.S. (2015). SIRT3 and SIRT5 regulate the enzyme activity and cardiolipin binding of very long-chain acyl-CoA dehydrogenase. PLoS One 10, e0122297.10.1371/journal.pone.0122297Search in Google Scholar PubMed PubMed Central

Zhang, C., Qu, S., Wei, X., Feng, Y., Zhu, H., Deng, J., Wang, K., Liu, K., Liu, M., Zhang, H., et al. (2016). HSP25 down-regulation enhanced p53 acetylation by dissociation of SIRT1 from p53 in DOX-induced H9c2 cell apoptosis. Cell Stress Chaperones 21, 251–260.10.1007/s12192-015-0655-3Search in Google Scholar PubMed PubMed Central

Zhou, S., Heller, L.J., and Wallace, K.B. (2001). Interference with calcium-dependent mitochondrial bioenergetics in cardiac myocytes isolated from DOX-treated rats. Toxicol. Appl. Pharmacol. 175, 60–67.10.1006/taap.2001.9230Search in Google Scholar PubMed

Received: 2016-10-21
Accepted: 2017-2-11
Published Online: 2017-6-23
Published in Print: 2017-8-28

©2017 Walter de Gruyter GmbH, Berlin/Boston

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