Abstract
Diallyl trisulfide (DATS) protects against apoptosis during myocardial ischemia-reperfusion (MI/R) injury in diabetic state, although the underlying mechanisms remain poorly defined. Previously, we and others demonstrated that silent information regulator 1 (SIRT1) activation inhibited oxidative stress and endoplasmic reticulum (ER) stress during MI/R injury. We hypothesize that DATS reduces diabetic MI/R injury by activating SIRT1 signaling. Streptozotocin (STZ)-induced type 1 diabetic rats were subjected to MI/R surgery with or without perioperative administration of DATS (40 mg/kg). We found that DATS treatment markedly improved left ventricular systolic pressure and the first derivative of left ventricular pressure, reduced myocardial infarct size as well as serum creatine kinase and lactate dehydrogenase activities. Furthermore, the myocardial apoptosis was also suppressed by DATS as evidenced by reduced apoptotic index and cleaved caspase-3 expression. However, these effects were abolished by EX527 (the inhibitor of SIRT1 signaling, 5 mg/kg). We further found that DATS effectively upregulated SIRT1 expression and its nuclear distribution. Additionally, PERK/eIF2α/ATF4/CHOP-mediated ER stress-induced apoptosis was suppressed by DATS treatment. Moreover, DATS significantly activated Nrf-2/HO-1 antioxidant signaling pathway, thus reducing Nox-2/4 expressions. However, the ameliorative effects of DATS on oxidative stress and ER stress-mediated myocardial apoptosis were inhibited by EX527 administration. Taken together, these data suggest that perioperative DATS treatment effectively ameliorates MI/R injury in type 1 diabetic setting by enhancing cardiac SIRT1 signaling. SIRT1 activation not only upregulated Nrf-2/HO-1-mediated antioxidant signaling pathway but also suppressed PERK/eIF2α/ATF4/CHOP-mediated ER stress level, thus reducing myocardial apoptosis and eventually preserving cardiac function.
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References
Frier BM (2014) Hypoglycaemia in diabetes mellitus: epidemiology and clinical implications. Nat Rev Endocrinol 10(12):711–722. doi:10.1038/nrendo.2014.170
Jia G, DeMarco VG, Sowers JR (2016) Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy. Nat Rev Endocrinol 12(3):144–153. doi:10.1038/nrendo.2015.216
Lachin JM, Orchard TJ, Nathan DM (2014) Update on cardiovascular outcomes at 30 years of the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care 37(1):39–43. doi:10.2337/dc13-2116
Schnell O, Cappuccio F, Genovese S, Standl E, Valensi P, Ceriello A (2013) Type 1 diabetes and cardiovascular disease. Cardiovasc Diabetol 12:156. doi:10.1186/1475-2840-12-156
Shi Z, Fu F, Yu L, Xing W, Su F, Liang X, Tie R, Ji L, Zhu M, Yu J, Zhang H (2015) Vasonatrin peptide attenuates myocardial ischemia-reperfusion injury in diabetic rats and underlying mechanisms. Am J Physiol Heart Circ Physiol 308(4):H281–H290. doi:10.1152/ajpheart.00666.2014
Yu L, Liang H, Dong X, Zhao G, Jin Z, Zhai M, Yang Y, Chen W, Liu J, Yi W, Yang J, Yi D, Duan W, Yu S (2015) Reduced silent information regulator 1 signaling exacerbates myocardial ischemia-reperfusion injury in type 2 diabetic rats and the protective effect of melatonin. J Pineal Res 59(3):376–390. doi:10.1111/jpi.12269
Yu L, Fan C, Li Z, Zhang J, Xue X, Xu Y, Zhao G, Yang Y, Wang H (2016) Melatonin rescues cardiac thioredoxin system during ischemia-reperfusion injury in acute hyperglycemic state by restoring Notch1/Hes1/Akt signaling in a membrane receptor-dependent manner. J Pineal Res. doi:10.1111/jpi.12375
Cominacini L, Mozzini C, Garbin U, Pasini A, Stranieri C, Solani E, Vallerio P, Tinelli IA, Fratta Pasini A (2015) Endoplasmic reticulum stress and Nrf2 signaling in cardiovascular diseases. Free Radic Biol Med 88(Pt B):233–242. doi:10.1016/j.freeradbiomed.2015.05.027
Gao L, Zhao YC, Liang Y, Lin XH, Tan YJ, Wu DD, Li XZ, Ye BZ, Kong FQ, Sheng JZ, Huang HF (2016) The impaired myocardial ischemic tolerance in adult offspring of diabetic pregnancy is restored by maternal melatonin treatment. J Pineal Res 61(3):340–352. doi:10.1111/jpi.12351
Hardeland R (2016) Melatonin and the pathologies of weakened or dysregulated circadian oscillators. J Pineal Res. doi:10.1111/jpi.12377
Palmirotta R, Cives M, Della-Morte D, Capuani B, Lauro D, Guadagni F, Silvestris F (2016) Sirtuins and cancer: role in the epithelial-mesenchymal transition. Oxid Med Cell Longev 2016:3031459. doi:10.1155/2016/3031459
Yang Y, Duan W, Li Y, Jin Z, Yan J, Yu S, Yi D (2013) Novel role of silent information regulator 1 in myocardial ischemia. Circulation 128(20):2232–2240. doi:10.1161/circulationaha.113.002480
Winnik S, Auwerx J, Sinclair DA, Matter CM (2015) Protective effects of sirtuins in cardiovascular diseases: from bench to bedside. Eur Heart J 36(48):3404–3412. doi:10.1093/eurheartj/ehv290
Yu L, Li Q, Yu B, Yang Y, Jin Z, Duan W, Zhao G, Zhai M, Liu L, Yi D, Chen M, Yu S (2016) Berberine attenuates myocardial ischemia/reperfusion injury by reducing oxidative stress and inflammation Response: role of silent information regulator 1. Oxid Med Cell Longev 2016:1689602. doi:10.1155/2016/1689602
Yu L, Sun Y, Cheng L, Jin Z, Yang Y, Zhai M, Pei H, Wang X, Zhang H, Meng Q, Zhang Y, Yu S, Duan W (2014) Melatonin receptor-mediated protection against myocardial ischemia/reperfusion injury: role of SIRT1. J Pineal Res 57(2):228–238. doi:10.1111/jpi.12161
Guo R, Liu W, Liu B, Zhang B, Li W, Xu Y (2015) SIRT1 suppresses cardiomyocyte apoptosis in diabetic cardiomyopathy: an insight into endoplasmic reticulum stress response mechanism. Int J Cardiol 191:36–45. doi:10.1016/j.ijcard.2015.04.245
Wang HC, Pao J, Lin SY, Sheen LY (2012) Molecular mechanisms of garlic-derived allyl sulfides in the inhibition of skin cancer progression. Ann N Y Acad Sci 1271:44–52. doi:10.1111/j.1749-6632.2012.06743.x
Ryan EA, Pick ME, Marceau C (2001) Use of alternative medicines in diabetes mellitus. Diabet Med 18(3):242–245
Adaki S, Adaki R, Shah K, Karagir A (2014) Garlic: review of literature. Indian J Cancer 51(4):577–581. doi:10.4103/0019-509x.175383
Charron CS, Dawson HD, Novotny JA (2016) Garlic influences gene expression in vivo and in vitro. J Nutr 146(2):444S–449S. doi:10.3945/jn.114.202481
Huang YT, Yao CH, Way CL, Lee KW, Tsai CY, Ou HC, Kuo WW (2013) Diallyl trisulfide and diallyl disulfide ameliorate cardiac dysfunction by suppressing apoptotic and enhancing survival pathways in experimental diabetic rats. J Appl Physiol (1985) 114(3):402–410. doi:10.1152/japplphysiol.00672.2012
Gu X, Zhu YZ (2011) Therapeutic applications of organosulfur compounds as novel hydrogen sulfide donors and/or mediators. Expert Rev Clin Pharmacol 4(1):123–133. doi:10.1586/ecp.10.129
Shimizu Y, Nicholson CK, Lambert JP, Barr LA, Kuek N, Herszenhaut D, Tan L, Murohara T, Hansen JM, Husain A, Naqvi N, Calvert JW (2016) Sodium sulfide attenuates ischemic-induced heart failure by enhancing proteasomal function in an Nrf2-dependent manner. Circ Heart Fail 9(4):e002368. doi:10.1161/circheartfailure.115.002368
Xiao J, Zhu X, Kang B, Xu J, Wu L, Hong J, Zhang Y, Ni X, Wang Z (2015) Hydrogen sulfide attenuates myocardial hypoxia-reoxygenation injury by inhibiting autophagy via mTOR activation. Cell Physiol Biochem 37(6):2444–2453. doi:10.1159/000438597
Wu D, Hu Q, Liu X, Pan L, Xiong Q, Zhu YZ (2015) Hydrogen sulfide protects against apoptosis under oxidative stress through SIRT1 pathway in H9c2 cardiomyocytes. Nitric Oxide 46:204–212. doi:10.1016/j.niox.2014.11.006
Zheng M, Qiao W, Cui J, Liu L, Liu H, Wang Z, Yan C (2014) Hydrogen sulfide delays nicotinamide-induced premature senescence via upregulation of SIRT1 in human umbilical vein endothelial cells. Mol Cell Biochem 393(1–2):59–67. doi:10.1007/s11010-014-2046-y
Li X, Zhang KY, Zhang P, Chen LX, Wang L, Xie M, Wang CY, Tang XQ (2014) Hydrogen sulfide inhibits formaldehyde-induced endoplasmic reticulum stress in PC12 cells by upregulation of SIRT-1. PLoS ONE 9(2):e89856. doi:10.1371/journal.pone.0089856
Peschke E, Wolgast S, Bazwinsky I, Ponicke K, Muhlbauer E (2008) Increased melatonin synthesis in pineal glands of rats in streptozotocin induced type 1 diabetes. J Pineal Res 45(4):439–448. doi:10.1111/j.1600-079X.2008.00612.x
Tsai CY, Wang CC, Lai TY, Tsu HN, Wang CH, Liang HY, Kuo WW (2013) Antioxidant effects of diallyl trisulfide on high glucose-induced apoptosis are mediated by the PI3K/Akt-dependent activation of Nrf2 in cardiomyocytes. Int J Cardiol 168(2):1286–1297. doi:10.1016/j.ijcard.2012.12.004
Yu L, Liang H, Lu Z, Zhao G, Zhai M, Yang Y, Yang J, Yi D, Chen W, Wang X, Duan W, Jin Z, Yu S (2015) Membrane receptor-dependent Notch1/Hes1 activation by melatonin protects against myocardial ischemia-reperfusion injury: in vivo and in vitro studies. J Pineal Res 59(4):420–433. doi:10.1111/jpi.12272
Yu L, Fan C, Li Z, Zhang J, Xue X, Xu Y, Zhao G, Yang Y, Wang H (2017) Melatonin rescues cardiac thioredoxin system during ischemia-reperfusion injury in acute hyperglycemic state by restoring Notch1/Hes1/Akt signaling in a membrane receptor-dependent manner. J Pineal Res. doi:10.1111/jpi.12375
Zhao GL, Yu LM, Gao WL, Duan WX, Jiang B, Liu XD, Zhang B, Liu ZH, Zhai ME, Jin ZX, Yu SQ, Wang Y (2016) Berberine protects rat heart from ischemia/reperfusion injury via activating JAK2/STAT3 signaling and attenuating endoplasmic reticulum stress. Acta Pharmacol Sin 37(3):354–367. doi:10.1038/aps.2015.136
Wan X, Wen JJ, Koo SJ, Liang LY, Garg NJ (2016) SIRT1-PGC1alpha-NFkappaB pathway of oxidative and inflammatory stress during Trypanosoma cruzi infection: benefits of SIRT1-targeted therapy in improving heart function in chagas disease. PLoS Pathog 12(10):e1005954. doi:10.1371/journal.ppat.1005954
Liang J, Yuan X, Shi S, Wang F, Chen Y, Qu C, Chen J, Hu D, Yang B (2015) Effect and mechanism of fluoxetine on electrophysiology in vivo in a rat model of postmyocardial infarction depression. Drug Des Devel Ther 9:763–772. doi:10.2147/dddt.s75863
Yu L, Li B, Zhang M, Jin Z, Duan W, Zhao G, Yang Y, Liu Z, Chen W, Wang S, Yang J, Yi D, Liu J, Yu S (2016) Melatonin reduces PERK-eIF2alpha-ATF4-mediated endoplasmic reticulum stress during myocardial ischemia-reperfusion injury: role of RISK and SAFE pathways interaction. Apoptosis 21(7):809–824. doi:10.1007/s10495-016-1246-1
Lee Y, Gustafsson AB (2009) Role of apoptosis in cardiovascular disease. Apoptosis 14(4):536–548. doi:10.1007/s10495-008-0302-x
Kuo WW, Wang WJ, Tsai CY, Way CL, Hsu HH, Chen LM (2013) Diallyl trisufide (DATS) suppresses high glucose-induced cardiomyocyte apoptosis by inhibiting JNK/NFkappaB signaling via attenuating ROS generation. Int J Cardiol 168(1):270–280. doi:10.1016/j.ijcard.2012.09.080
Wu H, Ye M, Yang J, Ding J (2016) Endoplasmic reticulum stress-induced apoptosis: a possible role in myocardial ischemia-reperfusion injury. Int J Cardiol 208:65–66. doi:10.1016/j.ijcard.2016.01.119
Powolny AA, Singh SV (2008) Multitargeted prevention and therapy of cancer by diallyl trisulfide and related Allium vegetable-derived organosulfur compounds. Cancer Lett 269(2):305–314. doi:10.1016/j.canlet.2008.05.027
Tsai CY, Wen SY, Shibu MA, Yang YC, Peng H, Wang B, Wei YM, Chang HY, Lee CY, Huang CY, Kuo WW (2015) Diallyl trisulfide protects against high glucose-induced cardiac apoptosis by stimulating the production of cystathionine gamma-lyase-derived hydrogen sulfide. Int J Cardiol 195:300–310. doi:10.1016/j.ijcard.2015.05.111
Predmore BL, Kondo K, Bhushan S, Zlatopolsky MA, King AL, Aragon JP, Grinsfelder DB, Condit ME, Lefer DJ (2012) The polysulfide diallyl trisulfide protects the ischemic myocardium by preservation of endogenous hydrogen sulfide and increasing nitric oxide bioavailability. Am J Physiol Heart Circ Physiol 302(11):H2410–H2418. doi:10.1152/ajpheart.00044.2012
Polhemus DJ, Kondo K, Bhushan S, Bir SC, Kevil CG, Murohara T, Lefer DJ, Calvert JW (2013) Hydrogen sulfide attenuates cardiac dysfunction after heart failure via induction of angiogenesis. Circ Heart Fail 6(5):1077–1086. doi:10.1161/circheartfailure.113.000299
Lambert JP, Nicholson CK, Amin H, Amin S, Calvert JW (2014) Hydrogen sulfide provides cardioprotection against myocardial/ischemia reperfusion injury in the diabetic state through the activation of the RISK pathway. Med Gas Res 4(1):20. doi:10.1186/s13618-014-0020-0
Suo R, Zhao ZZ, Tang ZH, Ren Z, Liu X, Liu LS, Wang Z, Tang CK, Wei DH, Jiang ZS (2013) Hydrogen sulfide prevents H(2)O(2)-induced senescence in human umbilical vein endothelial cells through SIRT1 activation. Mol Med Rep 7(6):1865–1870. doi:10.3892/mmr.2013.1417
Ding M, Lei J, Han H, Li W, Qu Y, Fu E, Fu F, Wang X (2015) SIRT1 protects against myocardial ischemia-reperfusion injury via activating eNOS in diabetic rats. Cardiovasc Diabetol 14:143. doi:10.1186/s12933-015-0299-8
Tanno M, Sakamoto J, Miura T, Shimamoto K, Horio Y (2007) Nucleocytoplasmic shuttling of the NAD+-dependent histone deacetylase SIRT1. J Biol Chem 282(9):6823–6832. doi:10.1074/jbc.M609554200
Tanno M, Kuno A, Yano T, Miura T, Hisahara S, Ishikawa S, Shimamoto K, 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(11):8375–8382. doi:10.1074/jbc.M109.090266
Rosenberg MI, Parkhurst SM (2002) Drosophila Sir2 is required for heterochromatic silencing and by euchromatic Hairy/E(Spl) bHLH repressors in segmentation and sex determination. Cell 109(4):447–458
Chen IY, Lypowy J, Pain J, Sayed D, Grinberg S, Alcendor RR, Sadoshima J, Abdellatif M (2006) Histone H2A.z is essential for cardiac myocyte hypertrophy but opposed by silent information regulator 2alpha. J Biol Chem 281(28):19369–19377. doi:10.1074/jbc.M601443200
Tong C, Morrison A, Mattison S, Qian S, Bryniarski M, Rankin B, Wang J, Thomas DP, Li J (2013) Impaired SIRT1 nucleocytoplasmic shuttling in the senescent heart during ischemic stress. FASEB J 27(11):4332–4342. doi:10.1096/fj.12-216473
Peake BF, Nicholson CK, Lambert JP, Hood RL, Amin H, Amin S, Calvert JW (2013) Hydrogen sulfide preconditions the db/db diabetic mouse heart against ischemia-reperfusion injury by activating Nrf2 signaling in an Erk-dependent manner. Am J Physiol Heart Circ Physiol 304(9):H1215–H1224. doi:10.1152/ajpheart.00796.2012
Gao S, Yang Z, Shi R, Xu D, Li H, Xia Z, Wu QP, Yao S, Wang T, Yuan S (2016) Diabetes blocks the cardioprotective effects of sevoflurane postconditioning by impairing Nrf2/Brg1/HO-1 signaling. Eur J Pharmacol 779:111–121. doi:10.1016/j.ejphar.2016.03.018
Ding YW, Zhao GJ, Li XL, Hong GL, Li MF, Qiu QM, Wu B, Lu ZQ (2016) SIRT1 exerts protective effects against paraquat-induced injury in mouse type II alveolar epithelial cells by deacetylating NRF2 in vitro. Int J Mol Med 37(4):1049–1058. doi:10.3892/ijmm.2016.2503
Xue F, Huang JW, Ding PY, Zang HG, Kou ZJ, Li T, Fan J, Peng ZW, Yan WJ (2016) Nrf2/antioxidant defense pathway is involved in the neuroprotective effects of Sirt1 against focal cerebral ischemia in rats after hyperbaric oxygen preconditioning. Behav Brain Res 309:1–8. doi:10.1016/j.bbr.2016.04.045
Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (81500263, 81470411 and 81570232).
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The authors who participated in the research design were Liming Yu, Shu Li, Yang Yang and Huishan Wang. Liming Yu and Shu Li conducted experiments. Zhi Li, Jian Zhang, Xiaodong Xue, Liming Yu, Shu Li and Xinlong Tang performed the data analysis. Xinlong Tang, Liming Yu, Jinsong Han, Yu Liu, Yuji Zhang, Yong Zhang, Yinli Xu, Yang Yang and Huishan Wang wrote or contributed to the writing of the manuscript.
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Liming Yu, Shu Li, and Xinlong Tang have contributed equally to this work.
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10495_2017_1378_MOESM1_ESM.tif
The effects of EX527 treatment on cardiac function, apoptotic signaling and SIRT1 intracellular distribution in MI/R-injured diabetic heart. a Left ventricular systolic pressure (LVSP). b and c The first derivative of left ventricular pressure (+dP/dtmax and -dP/dtmax). d Representative blots. e Caspase-3 expression. f Cleaved caspase-3 expression. g Representative blots. h Cytoplasmic SIRT1 distribution. i Nuclear SIRT1 distribution. The results are expressed as the means ± SEM, n= 6/group. V, vehicle; MI/R, myocardial ischemia-reperfusion; DATS, diallyl trisulfide. Supplementary material 1 (TIF 834 KB).
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Yu, L., Li, S., Tang, X. et al. Diallyl trisulfide ameliorates myocardial ischemia–reperfusion injury by reducing oxidative stress and endoplasmic reticulum stress-mediated apoptosis in type 1 diabetic rats: role of SIRT1 activation. Apoptosis 22, 942–954 (2017). https://doi.org/10.1007/s10495-017-1378-y
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DOI: https://doi.org/10.1007/s10495-017-1378-y