Abstract
Objectives Myocardial ischemia/reperfusion injury remains an important clinical problem in the world. Extensive research have focused on strategies for attenuating myocardial ischemia and reperfusion injury. Danshensu (DSS) and tetramethylpyrazine (TMP) are important cardioprotective components isolated from the traditional Chinese herbs Danshen and Chuanxiong, respectively. D2T is a novel conjugate with two molecules of DSS introduced to a TMP through an ester bond. This study aims to explore the cardioprotection of D2T and its mechanisms of action.
Methods and Results H9c2 cardiomyocytes were treated with tert-butyl hydroperoxide(t-BHP) to induce oxidative stress in vitro. D2T pretreatment protected cardiomyocytes from t-BHP- induced oxidative injury and mitochondrial dysfunction. Western blot analysis showed that D2T activated phosphorylation of PI3K and Akt and induced HO-1 protein expression together with its upstream regulator Nrf2. Wortmannin, a phosphoinositide 3-kinase (PI3K) inhibitor, partially abolished the restoration of cell viability offered by D2T. In a rat myocardial ischemia and reperfusion model, intravenous D2T significantly reduced infarct size.
Conclusions The cardioprotection of D2T is mediated by inhibiting oxidative injury and mitochondrial dysfunction. D2T acts by the activation of PI3k/Akt and Nrf2/HO-1 signaling pathways, suggesting D2T may be an effective treatment for myocardial ischemia/reperfusion injury.
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References
Maeda K, Ruel M. Prevention of ischemia-reperfusion injury in cardiac surgery: therapeutic strategies targeting signaling pathways.J Thorac Cardiov Surg. 2014;149:910–911.
Hausenloy DJ, Yellon DM. Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Invest. 2013;123:92–100.
Navarro-Yepes J, Burns M, Anandhan A, Khalimonchuk O,del Razo LM, Quintanilla-Vega B, et al. Oxidative stress, redox signaling, and autophagy: cell death versus survival. Antioxid Redox Signal. 2014;21:66–85.
Kurian GA, Rajagopal R, Vedantham S, Rajesh M. The role of oxidative stress in myocardial ischemia and reperfusion injury and remodeling: revisited. Oxid Med Cell Longev. 2016;2016:1656450.
Zuo L, Zhou T, Pannell BK, Ziegler AC, Best TM. Biological and physiological role of reactive oxygen species—the good, the bad and the ugly. Acta Physiol (Oxf ). 2015;214:329–348.
Kurian GA, Paddikkala J. N-acetylcysteine and magnesium improve biochemical abnormalities associated with myocardial ischaemic reperfusion in South Indian patients undergoing coronary artery bypass grafting: a comparative analysis. Singapore Med J. 2010;51:381–388.
Cheng L, Jin Z, Zhao R, Ren K, Deng C, Yu S. Resveratrol attenuates inflammation and oxidative stress induced by myocardial ischemia-reperfusion injury: role of Nrf2/ARE pathway. Int J Clin Exp Med. 2015;8:10420–10428.
Wu M, Lu SJ, Zhong JG, Huang K, Zhang SD. Protective effects of pterostilbene against myocardial ischemia/reperfusion injury in rats. Inflammation. 2017;40:578–588.
Walters JW, Amos D, Ray K, Santanam N. Mitochondrial redox status as a target for cardiovascular disease. Curr OpinPharmacol. 2016;27:50–55.
Kalogeris T, Baines CP, Krenz M, Korthuis RJ. Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol. 2012;298:229–317.
Feng JY, Yang Y, Zhou YJ, Wang BD, Xiong HY, Fan CX, et al. Bakuchiol attenuates myocardial ischemia reperfusion injury by maintaining mitochondrial function: the role of silent information regulator 1. Apoptosis. 2016;21:532–545.
Zhou L, Zuo Z, Chow MS. Danshen: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use. J Clin Pharmacol. 2005;45:1345–1359.
Qian W, Xiong X, Fang Z, Lu H, Wang Z. Protective effect of tetramethylpyrazine on myocardial ischemia-reperfusion injury.Evid Based Complement Alternat Med. 2014;2014:107501.
Zhao BL, Jiang W, Zhao Y, Hou JW, Xin WJ. Scavenging effects of Salvia miltiorrhiza on free radicals and its protection for myocardial mitochondrial membranes from ischemia-reperfusion injury. Biochem Mol Biol Int. 1996;38:1171–1182.
Cao CM, Xia Q, Zhang X, Xu WH, Jiang HD, Chen JZ. Salvia miltiorrhiza attenuates the changes in contraction and intracellular calcium induced by anoxia and reoxygenation in rat cardiomyocytes. Life Sci. 2003;72:2451–2463.
Zhang ZH, Yu SZ, Wang ZT, Zhao BL, Hou JW, Yang FJ, et al. Scavenging effects of tetramethylpyrazine on active oxygen free radicals. Zhongguo Yao Li Xue Bao. 1994;15:229–231.
Guo M, Liu Y, Shi D. Cardiovascular Actions and Therapeutic Potential of Tetramethylpyrazine (Active Component Isolated from Rhizoma Chuanxiong): Roles and Mechanisms. Biomed Res Int. 2016;2016:2430329.
Zhang DW, Liu JG, Feng JT, Liang XM, Zhang L, Yang XP, et al. Effects of effective components Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. extracts of Salviae Miltiorrhizae and Rhizoma Chuanxiong on rat myocardial ischemia/reperfusion injury. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2010;22:109–112.
Jia Y, Leung SW, Lee MY, Cui G, Huang X, Pan F. The efficacy of guanxinning injection in treating angina pectoris: systematic review and meta-analysis of randomized controlled trials. Evid Based Complement Alternat Med. 2013;2013:282707.
Wang R, Han QH, Jia YP. Effect of danshen chuanxiongqin injection on the myocardial damage of unstable angina patients undergoing percutaneous coronary intervention. Zhongguo Zhong xi yijie he zazhi. 2011;31:899–902.
Josephson RA, Silverman HS, Lakatta EG, Stern MD, Zweier JL. Study of the mechanisms of hydrogen peroxide and hydroxyl free radical-induced cellular injury and calcium overload in cardiac myocytes. J Biol Chem. 1991;266:2354–2361.
Javadov S, Karmazyn M, Escobales N. Mitochondrial permeability transition pore opening as a promising therapeutic target in cardiac diseases. J Pharmacol Exp Ther. 2009;330:670–678.
Halestrap AP, Richardson AP. The mitochondrial permeability transition: a current perspective on its identity and
role in ischaemia/reperfusion injury. J Mol Cell Cardiol.2015;78:129–141.
Lee Y, Gustafsson AB. Role of apoptosis in cardiovascular disease. Apoptosis. 2009;14:536–548.
Esposti MD, Dive C. Mitochondrial membrane permeabilisation by Bax/Bak. Biochem Biophys Res Commun. 2003;304:455–461.
Guo L, Pietkiewicz D, Pavlov EV, Grigoriev SM, Kasianowicz JJ, Dejean LM, et al. Effects of cytochrome c on the mitochondrial apoptosis-induced channel MAC. Am J Physiol Cell Physiol.2004;286:C1109–C1117.
Scorrano L, Korsmeyer SJ. Mechanisms of cytochrome c release by proapoptotic BCL-2 family members. Biochem Biophys Res Commun. 2003;304:437–444.
Diestel A, Drescher C, Miera O, Berger F, Schmitt KRL. Hypothermia protects H9c2 cardiomyocytes from H2O2 induced apoptosis.Cryobiology. 2011;62:53–61.
Mikhailov V, Mikhailova M, Pulkrabek DJ, Dong Z,Venkatachalam MA, Saikumar P. Bcl-2 prevents Bax oligomerization in the mitochondrial outer membrane. J Biol Chem.2001;276:18361–18374.
Jun HO, Kim DH, Lee SW, Lee HS, Seo JH, Kim JH, et al. Clusterin protects H9c2 cardiomyocytes from oxidative stress-induced apoptosis via Akt/GSK-3? signaling pathway. Exp Mol Med.2011;43:53–61.
Tang D, Okada H, Ruland J, Liu L, Stambolic V, Mak TW, et al.Akt is activated in response to an apoptotic signal. J Biol Chem.2001;276:30461–30466.
Miyamoto S, Murphy AN, Brown JH. Akt-mediated mitochondrial protection in the heart: metabolic and survival pathways to the rescue. J Bioenerg Biomembr. 2009;41:169–180.
Kennedy SG, Kandel ES, Cross TK, Hay N. Akt/Protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria. Mol Cell Biol. 1999;19:5800–5810.
Shah ZA, Li RC, Thimmulappa RK, Kensler KW, Yamamoto M, Biswal S, et al. Role of reactive oxygen species in modulation of Nrf2 following ischemic reperfusion injury. Neuroscience.2007;147:53–59.
Kim YM, Pae HO, Park JE, Lee YC, Woo JM, Kim NH, et al. Heme oxygenase in the regulation of vascular biology: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal. 2011;14:137–167.
Wang J, Hu X, Jiang H. Nrf-2-HO-1-HMGB1 axis: an important therapeutic approach for protection against myocardial ischemia and reperfusion injury. Int J Cardiol. 2014;172:223–224.
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- Cardioprotection of a Novel Danshensu Derivate Against Oxidative Injury and Mitochondrial Dysfunction in Vitro and Myocardial Ischemia/Reperfusion Injury in Rat
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