Protective effects of tanshinone IIA sodium sulfonate on ischemia-reperfusion-induced myocardial injury in rats

Document Type : Original Article


1 Department of Emergency, The First Affiliated Hospital, Soochow University, 188 Shi-Zi Road, Suzhou 215006, PR China

2 Department of Emergency, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, P.R. China

3 Department of Internal Medicine, The Affiliated Suzhou Chinese Traditional Medicine Hospital, Nanjing University of Chinese Medicine, Yang-Su Road, Suzhou 215003, P.R. China

4 Department of Physiology, Medical College of Soochow University, 199 Ren-Ai Road, Dushu Lake Campus, Suzhou Industrial Park, Suzhou 215123, P.R. China


Objective(s): This study investigated the protective effect of tanshinone IIA sodium sulfonate (TSS) on ischemia-reperfusion (I/R) induced cardiac injury, and the underlying mechanism of action.
Materials and Methods:Male Sprague-Dawley rats were subjected to a 30-min coronary arterial occlusion followed by 24 hours' reperfusion. Half an hour before the left coronary artery ligation, rats were pretreated with TSS in three different dosages (15, 30, 70 mg/kg, IP). Twenty-four hours later, cardiac function was measured and the ratio of infarct size to area at risk (AAR) was calculated. Western blotting examined the expression of the inflammatory mediator high-mobility group box1 (HMGB-1), anti-apoptotic protein Bcl-2, pro-apoptotic mediators such as Bax and Caspase-3, markers of autophagy such as ratio of LC3B/LC3A and Beclin-1 expression.
Results: Our results showed that TSS dose-dependently improves cardiac function, accompanied with decrease of HMGB1 level, increase of LC3B/LC3A ratio and increase of Beclin-1 expression. TSS treatment down-regulates Bax and Caspase-3 expression, while up-regulating Bcl-2 levels.
Conclusion: TSS ameliorates I/R induced myocardial injury and improves cardiac function via reducing inflammation and apoptosis, while enhancing autophagy.


1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, et al. Heart disease and stroke statistics--2013 update: a report from the American Heart Association. Circulation. 2013;127(1):e6.
2. Lopez AD, Murray CC. The global burden of disease, 1990-2020. Nat Med 1998; 4:1241-1243.
3. Hausenloy DJ, Yellon DM. Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Invest 2013; 123:92-100.
4. Murphy E, Steenbergen C. Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev 2008; 88:581-609.
5. Jordan JE, Zhao ZQ, Vinten-Johansen J. The role of neutrophils in myocardial ischemia-reperfusion injury. Cardiovasc Res 1999; 43:860-878.
6. Kwak W, Ha YS, Soni N, Lee W, Park S-I, Ahn H, et al. Apoptosis imaging studies in various animal models using radio-iodinated peptide. Apoptosis 2015; 20:110-121.
7. Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, Yamagata H, et al. Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 2005; 434:652-658.
8. Zhai C-l, Zhang M-q, Zhang Y, Xu H-x, Wang J-m, An G-p, et al. Glycyrrhizin protects rat heart against ischemia-reperfusion injury through blockade of HMGB1-dependent phospho-JNK/Bax pathway. Acta Pharmacol Sin 2012; 33:1477-1487.
9. Ding H-S, Yang J, Chen P, Yang J, Bo S-Q, Ding J-W, et al. The HMGB1-TLR4 axis contributes to myocardial ischemia/reperfusion injury via regulation of cardiomyocyte apoptosis. Gene. 2013; 527:389-393.
10. Depre C, Vatner SF. Cardioprotection in stunned and hibernating myocardium. Heart Fail Rev 2007; 12:307-317.
11. Ma X, Liu H, Foyil SR, Godar RJ, Weinheimer CJ, Diwan A. Autophagy is impaired in cardiac ischemia-reperfusion injury. Autophagy 2012; 8:1394-1396.
12. Ma X, Liu H, Foyil SR, Godar RJ, Weinheimer CJ, Hill JA, et al. Impaired autophagosome clearance contributes to cardiomyocyte death in ischemia/reperfusion injury. Circulation 2012; 125:3170-3181.
13. Chen C, Hu L-X, Dong T, Wang G-Q, Wang L-H, Zhou X-P, et al. Apoptosis and autophagy contribute to gender difference in cardiac ischemia–reperfusion induced injury in rats. Life Sci 2013; 93:265-270.
14. Przyklenk K, Undyala VV, Wider J, Sala-Mercado JA, Gottlieb RA, Mentzer RM, Jr. Acute induction of autophagy as a novel strategy for cardioprotection: getting to the heart of the matter. Autophagy 2011; 7:432-433.
15. Kai G, Xu H, Zhou C, Liao P, Xiao J, Luo X, et al. Metabolic engineering tanshinone biosynthetic pathway in Salvia miltiorrhiza hairy root cultures. Metab Eng 2011; 13:319-327.
16. Pan L-L, Liu X-H, Jia Y-L, Wu D, Xiong Q-H, Gong Q-H, et al. A novel compound derived from danshensu inhibits apoptosis via upregulation of heme oxygenase-1 expression in SH-SY5Y cells. Biochim Biophys Acta 2013; 1830:2861-2871.
17. Wu G-b, Zhou E-x, Qing D-x. Tanshinone II (A ) elicited vasodilation in rat coronary arteriole: Roles of nitric oxide and potassium channels. Eur J Pharmacol 2009; 617:102-107.
18. Yin Y, Guan Y, Duan J, Wei G, Zhu Y, Quan W, et al. Cardioprotective effect of Danshensu against myocardial ischemia/reperfusion injury and inhibits apoptosis of H9c2 cardiomyocytes via Akt and ERK1/2 phosphorylation. Eur J Pharmacol 2013; 699:219-226.
19. Wei B, Li WW, Ji J, Hu QH, Ji H. The cardioprotective effect of sodium tanshinone IIA sulfonate and the optimizing of therapeutic time window in myocardial ischemia/reperfusion injury in rats. Atherosclerosis 2014; 235:318-327.
20. Zhang G-X, Kimura S, Murao K, Obata K, Matsuyoshi H, Takaki M. Inhibition of cytochrome c release by 10-N-nonyl acridine orange, a cardiolipin-specific dye, during myocardial ischemia-reperfusion in the rat. Am J Physiol Heart Circ Physiol 2010; 298:H433-H439.
21. Yang R, Liu A, Ma X, Li L, Su D, Liu J. Sodium tanshinone IIA sulfonate protects cardiomyocytes against oxidative stress-mediated apoptosis through inhibiting JNK activation. J Cardiovasc Pharmacol 2008; 51:396-401.
22. Scarfò L, Ghia P. Reprogramming cell death: BCL2 family inhibition in hematological malignancies. Immunol Lett 2013; 155:36-39.
23. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007; 357:1121-35.
24. Dominguez-Rodriguez A, Abreu-Gonzalez P, Reiter RJ. Cardioprotection and pharmacological therapies in acute myocardial infarction: Challenges in the current era. World J Cardiol 2014; 6:100-106.
25. Zhang M-q, Zheng Y-l, Chen H, Tu J-f, Shen Y, Guo J-p, et al. Sodium tanshinone IIA sulfonate protects rat myocardium against ischemia-reperfusion injury via activation of PI3K/Akt/FOXO3A/Bim pathway. Acta Pharmacol Sin 2013; 34:1386-1396.
26. Bagai A, Dangas GD, Stone GW, Granger CB. Reperfusion strategies in acute coronary syndromes. Circ Res 2014;114:1918-1928.
27. Xu T, Wu X, Chen Q, Zhu S, Liu Y, Pan D, et al. The Anti-Apoptotic and Cardioprotective Effects of Salvianolic Acid A on Rat Cardiomyocytes following Ischemia/Reperfusion by DUSP-Mediated Regulation of the ERK1/2/JNK Pathway. PLoS One 2014; 9:e102292
28. Umansky SR, Cuenco GM, Khutzian SS, Barr PJ, Tomei LD. Post-ischemic apoptotic death of rat neonatal cardiomyocytes. Cell Death Differ 1995; 2:235-241.
29. Decker RS, Wildenthal K. Lysosomal alterations in hypoxic and reoxygenated hearts. I. Ultrastructural and cytochemical changes. Am J Pathol 1980; 98:425-444.
30. Hamacher-Brady A, Brady NR, Logue SE, Sayen MR, Jinno M, Kirshenbaum LA, et al. Response to myocardial ischemia/reperfusion injury involves Bnip3 and autophagy. Cell Death Differ 2007; 14:146-157.
31. Russell RR, 3rd, Li J, Coven DL, Pypaert M, Zechner C, Palmeri M, et al. AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Invest. 2004; 114:495-503.
32. Yang H, Antoine DJ, Andersson U, Tracey KJ. The many faces of HMGB1: molecular structure-functional activity in inflammation, apoptosis, and chemotaxis. J Leukoc Biol 2013; 93:865-873.
33. Hu X, Zhou X, He B, Xu C, Wu L, Cui B, et al. Minocycline protects against myocardial ischemia and reperfusion injury by inhibiting high mobility group box 1 protein in rats. Eur J Pharmacol 2010; 638:84-89.
34. Sun X, Tang D. HMGB1-dependent and-independent autophagy. Autophagy 2014;10:1873-1976.
35. Yu Q, Chen H, Sheng L, Liang Y, Li Q. Sodium tanshinone IIA sulfonate prolongs the survival of skin allografts by inhibiting inflammatory cell infiltration and T cell proliferation. Int Immunopharmacol 2014; 22: 277-284.
36. Sun N, Li E, Wang Z, Zhao J, Wang S, He J, et al. Sodium tanshinone IIA sulfonate inhibits porcine reproductive and respiratory syndrome virus via suppressing N gene expression and blocking virus-induced apoptosis. Antivir Ther 2014; 19:89-95.
37. Liu HC, Liu HH. [Adverse reactions of tanshinone II(A) sodium sulfonate injection in treating 18 cases: an analysis of clinical features]. Zhongguo Zhong Xi Yi Jie He Za Zhi 2013; 33:1287-1289.