Research progress of tanshinone <b>Ⅱ</b>A in cardiovascular diseases_West China Medical Journal

Authors：

LONG Xiupeng ¹ , ZENG Yuting ¹ , TAO Shun ¹ ,  ZHANG Zhe ²

1. School of Medicine, Hunan University of Medicine, Huaihua, Hunan 418099, P. R. China;
2. Department of Cardiology, Shenzhen People’s Hospital, Shenzhen, Guangdong 518020, P. R. China;

Corresponding author：

ZHANG Zhe, Email: zhangzhe292@126.com

Keywords：

Tanshinone ⅡA; cardiovascular diseases; clinical trials; research progress

DOI：

10.7507/1002-0179.202405163

Video：

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Cardiovascular disease is one of the diseases with the highest morbidity and mortality in the world. Tanshinone ⅡA is one of the main active components of Salvia miltiorrhiza, which can significantly improve heart function. In this paper, the mechanisms of cardiovascular protection by tanshinone ⅡA are reviewed, including reducing myocardial apoptosis, inhibiting inflammatory reaction, improving atherosclerosis, and inhibiting myocardial fibrosis and antioxidant stress, and the related clinical research of tanshinone ⅡA is evaluated, so as to provide reference for the following research and clinical application of tanshinone ⅡA in cardiovascular system.

1.	Timmis A, Vardas P, Townsend N, et al. European Society of Cardiology: cardiovascular disease statistics 2021. Eur Heart J, 2022, 43(8): 716-799.
2.	Mkoko P, Bahiru E, Ajijola OA, et al. Cardiac arrhythmias in low- and middle-income countries. Cardiovasc Diagn Ther, 2020, 10(2): 350-360.
3.	中国心血管健康与疾病报告编写组. 中国心血管健康与疾病报告 2022 概要. 中国循环杂志, 2023, 38(6): 583-612.
4.	Li ZM, Xu SW, Liu PQ. Salvia miltiorrhiza Burge (Danshen): a golden herbal medicine in cardiovascular therapeutics. Acta Pharmacol Sin, 2018, 39(5): 802-824.
5.	Zhou ZY, Zhao WR, Zhang J, et al. Sodium tanshinone IIA sulfonate: a review of pharmacological activity and pharmacokinetics. Biomed Pharmacother, 2019, 118: 109362.
6.	Xu L, He D, Wu Y, et al. Tanshinone IIA inhibits cardiomyocyte apoptosis and rescues cardiac function during doxorubicin-induced cardiotoxicity by activating the DAXX/MEK/ERK1/2 pathway. Phytomedicine, 2022, 107: 154471.
7.	Chou SL, Ramesh S, Kuo CH, et al. Tanshinone IIA inhibits Leu27IGF-II-induced insulin-like growth factor receptor II signaling and myocardial apoptosis via estrogen receptor-mediated Akt activation. Environ Toxicol, 2022, 37(1): 142-150.
8.	Deng H, Yu B, Li Y. Tanshinone IIA alleviates acute ethanol-induced myocardial apoptosis mainly through inhibiting the expression of PDCD4 and activating the PI3K/Akt pathway. Phytother Res, 2021, 35(8): 4309-4323.
9.	Zhang MQ, Zheng YL, Chen H, 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(11): 1386-1396.
10.	Wu S, Lu D, Gajendran B, et al. Tanshinone IIA ameliorates experimental diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress in cardiomyocytes via SIRT1. Phytother Res, 2023, 37(8): 3543-3558.
11.	Fang Y, Duan C, Chen S, et al. Tanshinone-IIA inhibits myocardial infarct via decreasing of the mitochondrial apoptotic signaling pathway in myocardiocytes. Int J Mol Med, 2021, 48(2): 158.
12.	Zhong J, Ouyang H, Sun M, et al. Tanshinone IIA attenuates cardiac microvascular ischemia-reperfusion injury via regulating the SIRT1-PGC1α-mitochondrial apoptosis pathway. Cell Stress Chaperones, 2019, 24(5): 991-1003.
13.	Xuan Y, Yu C, Ni K, et al. Protective effects of tanshinone IIA on Porphyromonas gingivalis-induced atherosclerosis via the downregulation of the NOX2/NOX4-ROS mediation of NF-κB signaling pathway. Microbes Infect, 2023, 25(8): 105177.
14.	Li HL, Li T, Chen ZQ, et al. Tanshinone IIA reduces pyroptosis in rats with coronary microembolization by inhibiting the TLR4/MyD88/NF-κB/NLRP3 pathway. Korean J Physiol Pharmacol, 2022, 26(5): 335-345.
15.	Li D, Yang Z, Gao S, et al. Tanshinone IIA ameliorates myocardial ischemia/reperfusion injury in rats by regulation of NLRP3 inflammasome activation and Th17 cells differentiation. Acta Cir Bras, 2022, 37(7): e370701.
16.	Chen P, An Q, Huang Y, et al. Prevention of endotoxin-induced cardiomyopathy using sodium tanshinone IIA sulfonate: involvement of augmented autophagy and NLRP3 inflammasome suppression. Eur J Pharmacol, 2021, 909: 174438.
17.	He L, Liu YY, Wang K, et al. Tanshinone IIA protects human coronary artery endothelial cells from ferroptosis by activating the NRF2 pathway. Biochem Biophys Res Commun, 2021, 20: 575: 1-7.
18.	Tsai YT, Loh SH, Lee CY, et al. Tanshinone IIA inhibits high glucose-induced collagen synthesis via nuclear factor erythroid 2-related factor 2 in cardiac fibroblasts. Cell Physiol Biochem, 2018, 51(5): 2250-2261.
19.	Liu J, Zhou X, Meng Q, et al. AFC1 compound attenuated MI/R-induced ventricular remodeling via inhibiting PDGFR and STAT pathway. Front Pharmacol, 2019, 10: 1142.
20.	Qiao P, Xu J, Liu X, et al. Tanshinone IIA improves ventricular remodeling following cardiac infarction by regulating miR-205-3p. Dis Markers, 2021, 2021: 8740831.
21.	Yan N, Xiao C, Wang X, et al. Tanshinone IIA from Salvia miltiorrhiza exerts anti-fibrotic effects on cardiac fibroblasts and rat heart tissues by suppressing the levels of pro-fibrotic factors: the key role of miR-618. J Food Biochem, 2022, 46(2): e14078.
22.	Zhu J, Chen H, Guo J, et al. Sodium tanshinone IIA sulfonate inhibits vascular endothelial cell pyroptosis via the AMPK signaling pathway in atherosclerosis. J Inflamm Res, 2022, 15: 6293-6306.
23.	Wang H, Zhong L, Mi S, et al. Tanshinone IIA prevents platelet activation and down-regulates CD36 and MKK4/JNK2 signaling pathway. BMC Cardiovasc Disord, 2020, 20(1): 81.
24.	Wang J, Zhang Y, Feng X, D, et al. Tanshinone IIA alleviates atherosclerosis in LDLR^-/- mice by regulating efferocytosis of macrophages. Front Pharmacol, 2023, 14: 1233709.
25.	Li S, Yang K, Cao W, et al. Tanshinone IIA enhances the therapeutic efficacy of mesenchymal stem cells derived exosomes in myocardial ischemia/reperfusion injury via up-regulating miR-223-5p. J Control Release, 2023, 358: 13-26.
26.	Chen W, Li X, Guo S, et al. Tanshinone IIA harmonizes the crosstalk of autophagy and polarization in macrophages via miR-375/KLF4 pathway to attenuate atherosclerosis. Int Immunopharmacol, 2019, 70: 486-497.
27.	Tan YL, Ou HX, Zhang M, et al. Tanshinone IIA promotes macrophage cholesterol efflux and attenuates atherosclerosis of apoE^-/- mice by Omentin-1/ABCA1 pathway. Curr Pharm Biotechnol, 2019, 20(5): 422-432.
28.	Guo G, Zhao Q, Wang Q, et al. Tanshinone IIA ameliorate coxsackie virus B3-induced viral myocarditis through the inhibition of inflammation and modulation T helper 1/T helper 2 balance in mice. Pharmacology, 2019, 103(3/4): 136-142.
29.	Yan SH, Zhao NW, Geng ZR, et al. Modulations of Keap1-Nrf2 signaling axis by TIIA ameliorated the oxidative stress-induced myocardial apoptosis. Free Radic Biol Med, 2018, 115: 191-201.
30.	Zhang X, Wang Q, Wang X, et al. Tanshinone IIA protects against heart failure post-myocardial infarction via AMPKs/mTOR-dependent autophagy pathway. Biomed Pharmacother, 2019, 112: 108599.
31.	Hu T, Zou HX, Le SY, et al. Tanshinone IIA confers protection against myocardial ischemia/reperfusion injury by inhibiting ferroptosis and apoptosis via VDAC1. Int J Mol Med, 2023, 52(5): 109.
32.	Li K, Wang X, Fan C, et al. Tanshinone IIA promotes cardiac differentiation and improves cell motility by modulating the Wnt/β-catenin signaling pathway. Mol Med Rep, 2020, 22(3): 1839-1846.
33.	Zhang M, Chen Y, Chen H, et al. Tanshinone IIA alleviates cardiac hypertrophy through m6A modification of galectin-3. Bioengineered, 2022, 13(2): 4260-4270.
34.	Chen R, Chen W, Huang X, et al. Tanshinone IIA attenuates heart failure via inhibiting oxidative stress in myocardial infarction rats. Mol Med Rep, 2021, 23(6): 404.
35.	Lu TC, Wu YH, Chen WY, et al. Targeting oxidative stress and endothelial dysfunction using tanshinone IIA for the treatment of tissue inflammation and fibrosis. Oxid Med Cell Longev, 2022, 2022: 2811789.
36.	Shao H, Fang C, Huang Y, et al. Sodium tanshinone ⅡA sulfonate injection as adjunctive therapy for the treatment of heart failure: a systematic review and meta-analysis. Phytomedicine, 2022, 95: 153879.
37.	Zhou H, Zhao Y, Peng W, et al. Effect of sodium tanshinone IIA sulfonate injection on blood lipid in patients with coronary heart disease: a systematic review and meta-analysis of randomized clinical trials. Front Cardiovasc Med, 2021, 8: 770746.
38.	Peng L, Fan M, Li J, et al. Evidence quality assessment of sodium tanshinone IIA sulfonate injection intervention coronary heart disease angina pectoris: an overview of systematic reviews and meta-analyses. Medicine (Baltimore), 2023, 102(44): e35509.
39.	Wu X, Fan M, Wei S, et al. The efficacy and safety of sodium tanshinone ⅡA sulfonate injection in the treatment of unstable angina pectoris: a systematic review and meta-analysis. PLoS One, 2023, 18(8): e0290841.
40.	狄宁宁, 崔振川, 孙云静, 等. 丹参酮ⅡA 磺酸钠联合卡维地洛对心力衰竭患者心功能及内分泌激素水平的影响. 中国药业, 2021, 30(5): 51-54.
41.	Mao S, Wang L, Zhao X, et al. Efficacy of sodium tanshinone IIA sulfonate in patients with non-ST elevation acute coronary syndrome undergoing percutaneous coronary intervention: results from a multicentre, controlled, randomized trial. Cardiovasc Drugs Ther, 2021, 35(2): 321-329.
42.	Qiao YN, Zou YL, Guo SD. Low-density lipoprotein particles in atherosclerosis. Front Physiol, 2022, 13: 931931.
43.	Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement. Open Med, 2009, 3(3): e123-e130.
44.	温明韬, 许波, 李嘉程, 等. 丹参酮ⅡA 治疗血管系统损伤: 可能的分子机制及生物学过程. 中国组织工程研究, 2021, 25(35): 5656-5661.
45.	杨春昆, 潘清泉, 吉奎, 等. 川芎嗪对心血管的保护机制综述. 中国中药杂志, 2023, 48(6): 1446-1454.

1. Timmis A, Vardas P, Townsend N, et al. European Society of Cardiology: cardiovascular disease statistics 2021. Eur Heart J, 2022, 43(8): 716-799.
2. Mkoko P, Bahiru E, Ajijola OA, et al. Cardiac arrhythmias in low- and middle-income countries. Cardiovasc Diagn Ther, 2020, 10(2): 350-360.
3. 中国心血管健康与疾病报告编写组. 中国心血管健康与疾病报告 2022 概要. 中国循环杂志, 2023, 38(6): 583-612.
4. Li ZM, Xu SW, Liu PQ. Salvia miltiorrhiza Burge (Danshen): a golden herbal medicine in cardiovascular therapeutics. Acta Pharmacol Sin, 2018, 39(5): 802-824.
5. Zhou ZY, Zhao WR, Zhang J, et al. Sodium tanshinone IIA sulfonate: a review of pharmacological activity and pharmacokinetics. Biomed Pharmacother, 2019, 118: 109362.
6. Xu L, He D, Wu Y, et al. Tanshinone IIA inhibits cardiomyocyte apoptosis and rescues cardiac function during doxorubicin-induced cardiotoxicity by activating the DAXX/MEK/ERK1/2 pathway. Phytomedicine, 2022, 107: 154471.
7. Chou SL, Ramesh S, Kuo CH, et al. Tanshinone IIA inhibits Leu27IGF-II-induced insulin-like growth factor receptor II signaling and myocardial apoptosis via estrogen receptor-mediated Akt activation. Environ Toxicol, 2022, 37(1): 142-150.
8. Deng H, Yu B, Li Y. Tanshinone IIA alleviates acute ethanol-induced myocardial apoptosis mainly through inhibiting the expression of PDCD4 and activating the PI3K/Akt pathway. Phytother Res, 2021, 35(8): 4309-4323.
9. Zhang MQ, Zheng YL, Chen H, 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(11): 1386-1396.
10. Wu S, Lu D, Gajendran B, et al. Tanshinone IIA ameliorates experimental diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress in cardiomyocytes via SIRT1. Phytother Res, 2023, 37(8): 3543-3558.
11. Fang Y, Duan C, Chen S, et al. Tanshinone-IIA inhibits myocardial infarct via decreasing of the mitochondrial apoptotic signaling pathway in myocardiocytes. Int J Mol Med, 2021, 48(2): 158.
12. Zhong J, Ouyang H, Sun M, et al. Tanshinone IIA attenuates cardiac microvascular ischemia-reperfusion injury via regulating the SIRT1-PGC1α-mitochondrial apoptosis pathway. Cell Stress Chaperones, 2019, 24(5): 991-1003.
13. Xuan Y, Yu C, Ni K, et al. Protective effects of tanshinone IIA on Porphyromonas gingivalis-induced atherosclerosis via the downregulation of the NOX2/NOX4-ROS mediation of NF-κB signaling pathway. Microbes Infect, 2023, 25(8): 105177.
14. Li HL, Li T, Chen ZQ, et al. Tanshinone IIA reduces pyroptosis in rats with coronary microembolization by inhibiting the TLR4/MyD88/NF-κB/NLRP3 pathway. Korean J Physiol Pharmacol, 2022, 26(5): 335-345.
15. Li D, Yang Z, Gao S, et al. Tanshinone IIA ameliorates myocardial ischemia/reperfusion injury in rats by regulation of NLRP3 inflammasome activation and Th17 cells differentiation. Acta Cir Bras, 2022, 37(7): e370701.
16. Chen P, An Q, Huang Y, et al. Prevention of endotoxin-induced cardiomyopathy using sodium tanshinone IIA sulfonate: involvement of augmented autophagy and NLRP3 inflammasome suppression. Eur J Pharmacol, 2021, 909: 174438.
17. He L, Liu YY, Wang K, et al. Tanshinone IIA protects human coronary artery endothelial cells from ferroptosis by activating the NRF2 pathway. Biochem Biophys Res Commun, 2021, 20: 575: 1-7.
18. Tsai YT, Loh SH, Lee CY, et al. Tanshinone IIA inhibits high glucose-induced collagen synthesis via nuclear factor erythroid 2-related factor 2 in cardiac fibroblasts. Cell Physiol Biochem, 2018, 51(5): 2250-2261.
19. Liu J, Zhou X, Meng Q, et al. AFC1 compound attenuated MI/R-induced ventricular remodeling via inhibiting PDGFR and STAT pathway. Front Pharmacol, 2019, 10: 1142.
20. Qiao P, Xu J, Liu X, et al. Tanshinone IIA improves ventricular remodeling following cardiac infarction by regulating miR-205-3p. Dis Markers, 2021, 2021: 8740831.
21. Yan N, Xiao C, Wang X, et al. Tanshinone IIA from Salvia miltiorrhiza exerts anti-fibrotic effects on cardiac fibroblasts and rat heart tissues by suppressing the levels of pro-fibrotic factors: the key role of miR-618. J Food Biochem, 2022, 46(2): e14078.
22. Zhu J, Chen H, Guo J, et al. Sodium tanshinone IIA sulfonate inhibits vascular endothelial cell pyroptosis via the AMPK signaling pathway in atherosclerosis. J Inflamm Res, 2022, 15: 6293-6306.
23. Wang H, Zhong L, Mi S, et al. Tanshinone IIA prevents platelet activation and down-regulates CD36 and MKK4/JNK2 signaling pathway. BMC Cardiovasc Disord, 2020, 20(1): 81.
24. Wang J, Zhang Y, Feng X, D, et al. Tanshinone IIA alleviates atherosclerosis in LDLR^-/- mice by regulating efferocytosis of macrophages. Front Pharmacol, 2023, 14: 1233709.
25. Li S, Yang K, Cao W, et al. Tanshinone IIA enhances the therapeutic efficacy of mesenchymal stem cells derived exosomes in myocardial ischemia/reperfusion injury via up-regulating miR-223-5p. J Control Release, 2023, 358: 13-26.
26. Chen W, Li X, Guo S, et al. Tanshinone IIA harmonizes the crosstalk of autophagy and polarization in macrophages via miR-375/KLF4 pathway to attenuate atherosclerosis. Int Immunopharmacol, 2019, 70: 486-497.
27. Tan YL, Ou HX, Zhang M, et al. Tanshinone IIA promotes macrophage cholesterol efflux and attenuates atherosclerosis of apoE^-/- mice by Omentin-1/ABCA1 pathway. Curr Pharm Biotechnol, 2019, 20(5): 422-432.
28. Guo G, Zhao Q, Wang Q, et al. Tanshinone IIA ameliorate coxsackie virus B3-induced viral myocarditis through the inhibition of inflammation and modulation T helper 1/T helper 2 balance in mice. Pharmacology, 2019, 103(3/4): 136-142.
29. Yan SH, Zhao NW, Geng ZR, et al. Modulations of Keap1-Nrf2 signaling axis by TIIA ameliorated the oxidative stress-induced myocardial apoptosis. Free Radic Biol Med, 2018, 115: 191-201.
30. Zhang X, Wang Q, Wang X, et al. Tanshinone IIA protects against heart failure post-myocardial infarction via AMPKs/mTOR-dependent autophagy pathway. Biomed Pharmacother, 2019, 112: 108599.
31. Hu T, Zou HX, Le SY, et al. Tanshinone IIA confers protection against myocardial ischemia/reperfusion injury by inhibiting ferroptosis and apoptosis via VDAC1. Int J Mol Med, 2023, 52(5): 109.
32. Li K, Wang X, Fan C, et al. Tanshinone IIA promotes cardiac differentiation and improves cell motility by modulating the Wnt/β-catenin signaling pathway. Mol Med Rep, 2020, 22(3): 1839-1846.
33. Zhang M, Chen Y, Chen H, et al. Tanshinone IIA alleviates cardiac hypertrophy through m6A modification of galectin-3. Bioengineered, 2022, 13(2): 4260-4270.
34. Chen R, Chen W, Huang X, et al. Tanshinone IIA attenuates heart failure via inhibiting oxidative stress in myocardial infarction rats. Mol Med Rep, 2021, 23(6): 404.
35. Lu TC, Wu YH, Chen WY, et al. Targeting oxidative stress and endothelial dysfunction using tanshinone IIA for the treatment of tissue inflammation and fibrosis. Oxid Med Cell Longev, 2022, 2022: 2811789.
36. Shao H, Fang C, Huang Y, et al. Sodium tanshinone ⅡA sulfonate injection as adjunctive therapy for the treatment of heart failure: a systematic review and meta-analysis. Phytomedicine, 2022, 95: 153879.
37. Zhou H, Zhao Y, Peng W, et al. Effect of sodium tanshinone IIA sulfonate injection on blood lipid in patients with coronary heart disease: a systematic review and meta-analysis of randomized clinical trials. Front Cardiovasc Med, 2021, 8: 770746.
38. Peng L, Fan M, Li J, et al. Evidence quality assessment of sodium tanshinone IIA sulfonate injection intervention coronary heart disease angina pectoris: an overview of systematic reviews and meta-analyses. Medicine (Baltimore), 2023, 102(44): e35509.
39. Wu X, Fan M, Wei S, et al. The efficacy and safety of sodium tanshinone ⅡA sulfonate injection in the treatment of unstable angina pectoris: a systematic review and meta-analysis. PLoS One, 2023, 18(8): e0290841.
40. 狄宁宁, 崔振川, 孙云静, 等. 丹参酮ⅡA 磺酸钠联合卡维地洛对心力衰竭患者心功能及内分泌激素水平的影响. 中国药业, 2021, 30(5): 51-54.
41. Mao S, Wang L, Zhao X, et al. Efficacy of sodium tanshinone IIA sulfonate in patients with non-ST elevation acute coronary syndrome undergoing percutaneous coronary intervention: results from a multicentre, controlled, randomized trial. Cardiovasc Drugs Ther, 2021, 35(2): 321-329.
42. Qiao YN, Zou YL, Guo SD. Low-density lipoprotein particles in atherosclerosis. Front Physiol, 2022, 13: 931931.
43. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement. Open Med, 2009, 3(3): e123-e130.
44. 温明韬, 许波, 李嘉程, 等. 丹参酮ⅡA 治疗血管系统损伤: 可能的分子机制及生物学过程. 中国组织工程研究, 2021, 25(35): 5656-5661.
45. 杨春昆, 潘清泉, 吉奎, 等. 川芎嗪对心血管的保护机制综述. 中国中药杂志, 2023, 48(6): 1446-1454.

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