The cardioprotective effects of diallyl trisulfide on diabetic rats with ex vivo induced ischemia/reperfusion injury

  • Jovana N. Jeremic
  • Vladimir Lj. Jakovljevic
  • Vladimir I. Zivkovic
  • Ivan M. Srejovic
  • Jovana V. Bradic
  • Sergey Bolevich
  • Tamara R. Nikolic Turnic
  • Slobodanka Lj. Mitrovic
  • Nemanja U. Jovicic
  • Suresh C. Tyagi
  • Nevena S. JeremicEmail author


Diallyl trisulfide (DATS) is distinguished as the most potent polysulfide isolated from garlic. The aim of our study was to investigate effects of oral administration of DATS on healthy and diabetic rats, with special attention on heart function. Rats were randomly divided into four groups: CTRL (healthy rats), DATS (healthy rats treated with DATS), DM (diabetic rats), DM + DATS (diabetic rats treated with DATS). DATS (40 mg/kg of body weight) was administered every other day for 3 weeks, at the end of which rats underwent echocardiography, glycemic measurement and redox status assessment. Isolated rat hearts were subjected to 30 min global ischemia and 60 min reperfusion, after which heart tissue was counterstain with hematoxylin and eosin and cardiac Troponin T staining (cTnT), while expression of Bax, B cell lymphoma 2 (Bcl-2), caspase-3, caspase-9 and superoxide dismutase-2 were examined in the left ventricle. DATS treatment significantly reduced blood glucose levels of diabetic rats, and improved cardiac function recovery, diminished oxidation status, attenuated cardiac remodeling and inhibited myocardial apoptosis in healthy and diabetic rats. DATS treatment causes promising cardioprotective effects on ex vivo-induced ischemia/reperfusion (I/R) injury in diabetic and healthy rat heart probably mediated by inhibited myocardial apoptosis. Moreover, appropriate DATS consumption may provide potential co-therapy or prevention of hyperglycemia and various cardiac complications in rats with DM.


Cardioprotection Diallyl trisulfide Diabetes Ischemia–reperfusion injury Isolated heart 



This work was supported by Junior Project 03/18 by the Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.

Compliance with ethical standards

Conflict of interest

The authors have declared no conflict of interest.


  1. 1.
    Atkinson MA, Eisenbarth GS, Michels AW (2013) Type 1 diabetes. Lancet 383:69–82CrossRefGoogle Scholar
  2. 2.
    Yu L, Li S, Tang X, Li Z, Zhang J, Xue X, Han J, Liu Y, Zhang Y, Zhang Y, Xu Y, Yang Y, Wang H (2017) 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 22:942–954CrossRefGoogle Scholar
  3. 3.
    Eidi A, Eidi M, Esmaeili E (2006) Antidiabetic effect of garlic (Allium sativum L.) in normal and streptozotocin-induced diabetic rats. Phytomedicine 13:624–629CrossRefGoogle Scholar
  4. 4.
    Londhe VP (2011) Role of garlic (Allium sativum) in various diseases-an overview. J Pharm Res 4:129–134Google Scholar
  5. 5.
    Bradley JM, Organ CL, Lefer DJ (2016) Garlic-derived organic polysulfides and myocardial protection. J Nutr 146:403S–409SCrossRefGoogle Scholar
  6. 6.
    Liu CT, Hse H, Lii CK, Chen PS, Sheen LY (2005) Effects of garlic oil and diallyl trisulfide on glycemic control in diabetic rats. Eur J Pharmacol 516:165–173CrossRefGoogle Scholar
  7. 7.
    Huang YT, Yao CH, Way CL, Lee KW, Tsai CY, Ou HC, Kuo WW (2012) Diallyl trisulfide and diallyl disulfide ameliorate cardiac dysfunction by suppressing apoptotic and enhancing survival pathways in experimental diabetic rats. J App Physiol 114:402–410CrossRefGoogle Scholar
  8. 8.
    Chen YL, Chen Q, Cheng YF, Jin HH, Kong DS, Zhang F, Wu L, Shao JJ, Zheng SZ (2016) Diallyl trisulfide attenuates ethanol-induced hepatic steatosis by inhibiting oxidative stress and apoptosis. Biomed Pharmacother 79:35–43CrossRefGoogle Scholar
  9. 9.
    Kuo WW, Wang WJ, Tsai CY, Way CL, Hsu HH, Chen LM (2013) Diallyl trisulfide (DATS) suppresses high glucose-induced cardiomyocyte apoptosis by inhibiting JNK/NFκB signaling via attenuating ROS generation. Int J Cardiol 168:270–280CrossRefGoogle Scholar
  10. 10.
    Bell RM, Mocanu MM, Yellon DM (2011) Retrograde heart perfusion: the Langendorff technique of isolated heart perfusion. J Mol Cell Cardiol 50:940–950CrossRefGoogle Scholar
  11. 11.
    Jeremic J, Nikolic Turnic T, Zivkovic V, Jeremic N, Milosavljevic I, Srejovic I, Obrenovic R, Jancic S, Rakocevic M, Matic S, Djuric D, Jakovljevic V (2018) Vitamin B complex mitigates cardiac dysfunction in high-methionine diet-induced hyperhomocysteinemia. Clin Exp Pharmacol Physiol 45:683–693CrossRefGoogle Scholar
  12. 12.
    Wu CC, Sheen LY, Chen HW, Kuo WW, Tsai SJ, Lii CK (2002) Differential effects of garlic oil and its three major organosulfur components on the hepatic detoxification system in rats. J Agric Food Chem 50:378–383CrossRefGoogle Scholar
  13. 13.
    Chang MLW, Johnson MA (1980) Effect of garlic on carbohydrate metabolism and lipid synthesis in rats. J Nutr 110:931–936CrossRefGoogle Scholar
  14. 14.
    Polhemus D, Kondo K, Bhushan S, Bir SC, Kevil CG, Murohara T, Lefer DJ, Calvert JW (2013) Hydrogen sulfide attenuates cardiac dysfunction following heart failure via induction of angiogenesis. Circ Heart Fail 6:1077–1086CrossRefGoogle Scholar
  15. 15.
    Xu W, Wu W, Chen J, Guo R, Lin J, Liao X, Feng J (2013) Exogenous hydrogen sulfide protects H9c2 cardiac cells against high glucose-induced injury by inhibiting the activities of the p38MAPK and ERK1/2 pathways. Int J Mol Med 32:917–925CrossRefGoogle Scholar
  16. 16.
    Wei WB, Hu X, Zhuang XD, Liao LZ, Li WD (2014) GYY4137, a novel hydrogen sulfide-releasing molecule, likely protects against high glucose-induced cytotoxicity by activation of the AMPK/mTOR signal pathway in H9c2 cells. Mol Cell Biochem 389:249–256CrossRefGoogle Scholar
  17. 17.
    Nie XM, Zhou YJ, Xie Y, Li YF, Yang Q, Zhou ZM (2006) Effect of stent coated with diallyl trisulfide on endothelial structure and function after coronary injury: experiment with dogs. Zhonghua Yi Xue Za Zhi 86:1125–1128Google Scholar
  18. 18.
    Predmore BL, Julian D, Cardounel AJ (2011) Hydrogen sulfide increases nitric oxide production from endothelial cells by an Akt-dependent mechanism. Front Physiol 2:104CrossRefGoogle Scholar
  19. 19.
    Calvert JW, Jha S, Gundewar S, Elrod JW, Ramachandran A, Pattillo CB, Kevil CG, Lefer DJ (2009) Hydrogen sulfide mediates cardioprotection through Nrf2 signaling. Circ Res 105:365–374CrossRefGoogle Scholar
  20. 20.
    Zhou X, An G, Lu X (2015) Hydrogen sulfide attenuates the development of diabetic cardiomyopathy. Clin Sci 128:325–335CrossRefGoogle Scholar
  21. 21.
    Elrod JW, Calvert JW, Morrison J, Doeller JE, Kraus DW, Tao L, Jiao X, Scalia R, Kiss L, Szabo C, Kimura H, Chow CW, Lefer DJ (2007) Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function. Proc Nat Acad Sci USA 104:15560–15565CrossRefGoogle Scholar
  22. 22.
    Yang Z, Yang C, Xiao L, Liao X, Lan A, Wang X, Guo R, Chen P, Hu C, Feng J (2011) Novel insights into the role of HSP90 in cytoprotection of H2S against chemical hypoxia-induced injury in H9c2 cardiac myocytes. Int J Mol Med 28:397–403Google Scholar
  23. 23.
    Luan HF, Zhao ZB, Zhao QH, Zhu P, Xiu MY, Ji Y (2012) Hydrogen sulfide postconditioning protects isolated rat hearts against ischemia and reperfusion injury mediated by the JAK2/STAT3 survival pathway. Braz J Med Biol Res 45:898–905CrossRefGoogle Scholar
  24. 24.
    Fishbein MC, Wang T, Matijasevic M, Hong L, Apple FS (2003) Myocardial tissue troponins T and I: an immunohistochemical study in experimental models of myocardial ischemia. Cardiovasc Pathol 12:65–71CrossRefGoogle Scholar
  25. 25.
    O’Brien PJ, Dameron GW, Beck ML, Kang YJ, Erickson BK, Di Battista TH, Miller KE, Jackson KN, Mittelstadt S (1977) Cardiac troponin T is a sensitive specific biomarker of cardiac injury in laboratory animals. Lab Anim Sci 47:5Google Scholar
  26. 26.
    Ricchiuti V, Sharkey SW, Murakami MM, Voss EM, Apple FS (1998) Cardiac troponin I and T alterations in dog hearts with myocardial infarction: correlation with infarct size. Am J Clin Pathol 110:241–247CrossRefGoogle Scholar
  27. 27.
    Sun X, Wang W, Dai J, Jin S, Huang J, Guo C, Wang C, Pang L, Wang Y (2017) A long-term and slow-releasing hydrogen sulfide donor protects against myocardial ischemia/reperfusion injury. Sci Rep 7:3541CrossRefGoogle Scholar
  28. 28.
    Predmore BL, Kondo K, Bhushan S, Zlatokopsky MA, King AL, Aragon JP, Grinsfelder BD, 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:H2410–H2418CrossRefGoogle Scholar
  29. 29.
    Khatua TN, Adela R, Banerjee SK (2013) Garlic and cardioprotection: insights into the molecular mechanisms. Can J Physiol Pharmacol 91:448–458CrossRefGoogle Scholar
  30. 30.
    Liang D, Wu H, Wong MW, Huang D (2015) Diallyl trisulfide is a fast H2S donor, but diallyl disulfide is a slow one: the reaction pathways and intermediates of glutathione with polysulfides. Org Lett 17:4196–4199CrossRefGoogle Scholar
  31. 31.
    Shukla Y, Kalra N (2007) Cancer chemoprevention with garlic and its constituents. Cancer Lett 247:167–181CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Jovana N. Jeremic
    • 1
  • Vladimir Lj. Jakovljevic
    • 2
    • 3
  • Vladimir I. Zivkovic
    • 2
  • Ivan M. Srejovic
    • 2
  • Jovana V. Bradic
    • 1
  • Sergey Bolevich
    • 3
  • Tamara R. Nikolic Turnic
    • 1
  • Slobodanka Lj. Mitrovic
    • 4
  • Nemanja U. Jovicic
    • 5
  • Suresh C. Tyagi
    • 6
  • Nevena S. Jeremic
    • 1
    Email author
  1. 1.Department of Pharmacy, Faculty of Medical SciencesUniversity of KragujevacKragujevacSerbia
  2. 2.Department of Physiology, Faculty of Medical SciencesUniversity of KragujevacKragujevacSerbia
  3. 3.Department of Human Pathology, 1st Moscow State MedicalUniversity IM SechenovMoscowRussia
  4. 4.Department of Pathology, Faculty of Medical SciencesUniversity of KragujevacKragujevacSerbia
  5. 5.Department of Histology and Embryology, Faculty of Medical SciencesUniversity of KragujevacKragujevacSerbia
  6. 6.Department of Physiology, School of MedicineUniversity of LouisvilleLouisvilleUSA

Personalised recommendations