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Mitigation of H2O2-induced autophagic cell death by propofol in H9c2 cardiomyocytes

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Abstract

Autophagy, a self-eating process, is responsible for degradation of long-lived proteins and damaged cellular proteins/organelles. Double-membrane autophagosomes, formed during the process, engulf proteins/organelles and fuse with lysosomes to degrade the contents. It is important to maintain cell homeostasis and many physiological processes including cellular responses to oxidative stress. Oxidative stress induced by myocardial infarction is a major factor of heart failures. In this study, we examined how propofol modulates hydrogen peroxide (H2O2)-induced autophagic cell death in H9c2 cardiomyocytes. H2O2 dramatically induced cell death, which was similarly reduced in the presence of either propofol or autophagy inhibitors (e.g., wortmannin), suggesting that propofol has a protective effect in H2O2-induced autophagic cell death. Acidic autophagic vacuoles were elevated in H2O2-treated H9c2 cells, but they were largely decreased in the presence of propofol. Furthermore, many autophagy-related proteins such as LC3-II, ATG proteins, p62, AMPK, and JNK were activated in H2O2-treated H9c2 cells and were significantly deactivated in the presence of propofol. These results show that propofol regulates oxidative stress-induced autophagic cell death in cardiomyocytes. We further suggest that propofol can act as a cardioprotectant in heart diseases.

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Abbreviations

AMPK:

5′ AMP-activated protein kinase

AO:

Acridine orange

ATG:

Autophagy-related gene

I/R:

Ischemia/reperfusion

JNK:

Janus kinase

MAPK:

Mitogen-activated protein kinase

MDC:

Monodansylacadaverine

mTOR:

Mammalian target of rapamycin

PARP:

Poly (ADP-ribose) polymerase

References

  • Arnaoutoglou H, Vretzakis G, Souliotis D, Cambili M, Galaris D, Papadopoulos G. The effects of propofol or sevoflurane on free radical production after tourniquet induced ischaemia-reperfusion injury during knee arthroplasty. Acta Anaesthesiol Belg. 2007;58:3–6.

    PubMed  CAS  Google Scholar 

  • Black SC. In vivo models of myocardial ischemia and reperfusion injury: application to drug discovery and evaluation. J Pharmacol Toxicol Meth. 2000;43:153–67.

    Article  CAS  Google Scholar 

  • Chen Y, McMillan-Ward E, Kong J, Israels SJ, Gibson SB. Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells. Cell Death Differ. 2008;15:171–82.

    Article  PubMed  CAS  Google Scholar 

  • Choi SL, Kim SJ, Lee KT, Kim J, Mu J, Birnbaum MJ, et al. The regulation of AMP-activated protein kinase by H(2)O(2). Biochem Biophys Res Comm. 2001;287:92–7.

    Article  PubMed  CAS  Google Scholar 

  • Cory S, Adams JM. The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Canc. 2002;2:647–56.

    Article  CAS  Google Scholar 

  • Dadakhujaev S, Noh HS, Jung EJ, Hah YS, Kim CJ, Kim DR. The reduced catalase expression in TrkA-induced cells leads to autophagic cell death via ROS accumulation. Exp Cell Res. 2008;314:3094–106.

    Article  CAS  Google Scholar 

  • Hein S, Arnon E, Kostin S, Schonburg M, Elsasser A, Polyakova V, et al. Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms. Circulation. 2003;107:984–91.

    Article  PubMed  Google Scholar 

  • Hwang J, Lee S, Lee JT, Kwon TK, Kim DR, Kim H, et al. Gangliosides induce autophagic cell death in astrocytes. Br J Pharmacol. 2010;159:586–603.

    Article  PubMed  CAS  Google Scholar 

  • Ichimura Y, Kominami E, Tanaka K, Komatsu M. Selective turnover of p62/A170/SQSTM1 by autophagy. Autophagy. 2008;4:1063–6.

    PubMed  CAS  Google Scholar 

  • Jin YC, Kim W, Ha YM, Shin IW, Sohn JT, Kim HJ, et al. Propofol limits rat myocardial ischemia and reperfusion injury with an associated reduction in apoptotic cell death in vivo. Vasc Pharmacol. 2009;50:71–7.

    Article  CAS  Google Scholar 

  • Kamiya T, Hara H, Yamada H, Imai H, Inagaki N, Adachi T. Cobalt chloride decreases EC-SOD expression through intracellular ROS generation and p38-MAPK pathways in COS7 cells. Free Radic Res. 2008;42:949–56.

    Article  PubMed  CAS  Google Scholar 

  • Kiffin R, Bandyopadhyay U, Cuervo AM. Oxidative stress and autophagy. Antioxidants and Redox Signaling. 2006;8:152–62.

    Article  PubMed  CAS  Google Scholar 

  • Kimes BW, Brandt BL. Properties of a clonal muscle cell line from rat heart. Exp Cell Res. 1976;98:367–81.

    Article  PubMed  CAS  Google Scholar 

  • Konishi H, Fujiyoshi T, Fykui Y, Matsuzaki H, Yamamoto T, Ono Y, et al. Activation of protein kinase B indeced by H2O2 and heat shock through distinct mechanisms dependent and independent of phosphpatidylinositol 3-kinase. J Biochem (Tokyo). 1999;126:1136–43.

    CAS  Google Scholar 

  • Kroemer G, Marino G, Levine B. Autophagy and the intergrated stress response. Mol cell. 2010;40:280–93.

    Article  PubMed  CAS  Google Scholar 

  • Kubota C, Torii S, Hou N, Saito N, Yoshimoto Y, Imai H, et al. Constitutive reactive oxygen species generation from autophagosome/lysosome in neuronal oxidative toxicity. J Biol Chem. 2010;285:667–74.

    Article  PubMed  CAS  Google Scholar 

  • Lang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G, et al. Protection against fatal Sindbis virus encephalitis by Beclin, a novel Bcl-2-interaction protein. J Virol. 1998;72:8586–96.

    Google Scholar 

  • Levine B, Yuan J. Autophagy in cell death: an innocent convict? J Clin Invest. 2005;115:2679–88.

    Article  PubMed  CAS  Google Scholar 

  • Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY, et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell. 2009;137:1062–75.

    Article  PubMed  CAS  Google Scholar 

  • Matsui Y, Nakano N, Shao D, Gao S, Luo W, Hong C, et al. Lats2 is a negative regulator of myocyte size in the heart. Circ Res. 2008;103:1309–18.

    Article  PubMed  CAS  Google Scholar 

  • Mizushima N, Levin B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature. 2008;451:1069–75.

    Article  PubMed  CAS  Google Scholar 

  • Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell. 2010;140:313–26.

    Article  PubMed  CAS  Google Scholar 

  • Noh HS, Shin IW, Ha JH, Hah YS, Baek SM, Kim DR. Propofol protects the autophagic cell death induced by the ischemia/reperfusion injury in rats. Mol Cells. 2010;30:455–60.

    Article  PubMed  CAS  Google Scholar 

  • Puissant A, Robert G, Fenouille N, Luciano F, Cassuto JP, Raynaud S, et al. Resveratrol promotes autophagic cell death in chronic myelogenous leukemia cells via JNK-mediated p62/SQSTM1 expression and AMPK activation. Canc Res. 2010;70:1042–52.

    Article  CAS  Google Scholar 

  • Ryter SW, Kim HP, Hoetzel A, Park JW, Nakahira K, Wang X, et al. Mechanisms of cell death in oxidative stress. Antioxidants and Redox Signaling. 2007;9:49–89.

    Article  PubMed  CAS  Google Scholar 

  • Semenza GL, Agani F, Feldser D, Iyer N, Kotch L, Laughner E, et al. Hypoxia, HIF-1, and the pathophysiology of common human diseases. Adv Exp Med Biol. 2000;475:123–30.

    Article  PubMed  CAS  Google Scholar 

  • Shimizu S, Konishi A, Nishida Y, Mizuta T, Nishina H, Yamamoto A, et al. Involvement of JNK in the regulation of autophagic cell death. Oncogene. 2010;29:2070–82.

    Article  PubMed  CAS  Google Scholar 

  • Shintani T, Klionsky DJ. Autophagy in health and disease: a double-edged sword. Science. 2004;306:990–5.

    Article  PubMed  CAS  Google Scholar 

  • Walsh SK, Hepburn CY, Kane KA, Wainwright CL. Acute administration of cannabidiol in vivo suppresses ischaemia-induced cardiac arrhythmias and reduces infarct size when given at reperfusion. Br J Pharmacol. 2010;160:1234–42.

    Article  PubMed  CAS  Google Scholar 

  • Wang X, McCullough KD, Franke TF, Holbrook NJ. Epidermal growth factor receptor-dependent Akt activation by oxidative stress enhances cell survival. J Biol Chem. 2000;275:14624–31.

    Article  PubMed  CAS  Google Scholar 

  • Wang H, Xue Z, Wang Q, Feng X, Shen Z. Propofol protects hepatic L02 cells from hydrogen peroxide-induced apoptosis via activation of extracellular signal-regulated kinases pathway. Anesth Analg. 2008;107:534–40.

    Article  PubMed  CAS  Google Scholar 

  • Wang B, Shravah J, Luo H, Raedschelders K, Chen DDY, Ansley DM. Propofol protects against hydrogen peroxide-induced injury in cardiac H9c2 cells via Akt activation and Bcl-2 up-regulation. Biochem Biophy Res Comm. 2009;389:105–11.

    Article  CAS  Google Scholar 

  • Wu X, Zheng Y, Cui Y, Zhu L, Lu Y, Chen H. Propofol attenuates oxidative stress-induced PC12 cell injury via p38 MAP kinase dependent pathway. Acta Pharmacol Sin. 2007;28:1123–8.

    Article  PubMed  CAS  Google Scholar 

  • Yang J, Klionsky DJ. Eaten alive: a history of macroautophagy. Nature Cell Biol. 2010;12:814–22.

    Article  PubMed  CAS  Google Scholar 

  • Zalckvar E, Berissi H, Eisenstein M, Kimchi A. Phosphorylation of Beclin 1 by DAP-kinase promotes autophagy by weakening its interactions with Bcl-2 and Bcl-XL. Autophagy. 2009;5:720–2.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by a grant from the Korea Health Care Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A080403) and a National Research Foundation of Korea grant funded by the Korean government (NRF-2009-0071600 and R13-2005-012-02002-0).

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Authors and Affiliations

  1. Department of Biochemistry, Gyeongsang National University School of Medicine, Jinju, Republic of Korea, 660-751

    Ji Hye Ha, Hae Sook Noh & Deok Ryong Kim

  2. Department Anesthesiology and Pain Medicine, Gyeongsang National University School of Medicine, Jinju, Republic of Korea, 660-751

    Il Woo Shin

  3. Department Internal Medicine, Gyeongsang National University School of Medicine, Jinju, Republic of Korea, 660-751

    Jong Ryeal Hahm

  4. Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Republic of Korea, 660-751

    Ji Hye Ha, Hae Sook Noh, Il Woo Shin, Jong Ryeal Hahm & Deok Ryong Kim

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  1. Ji Hye Ha
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Correspondence to Deok Ryong Kim.

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Ha, J.H., Noh, H.S., Shin, I.W. et al. Mitigation of H2O2-induced autophagic cell death by propofol in H9c2 cardiomyocytes. Cell Biol Toxicol 28, 19–29 (2012). https://doi.org/10.1007/s10565-011-9202-x

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  • DOI: https://doi.org/10.1007/s10565-011-9202-x

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