Assessment of Tanshinone IIA Derivatives for Cardioprotection in Myocardial Ischemic Injury

Abstract

Tanshinone ⅡA (TSA), a component of traditional Chinese medicine, effectively protects against myocardial injury. However, its clinical application is limited by poor water solubility and a short half-life. In this study, we report on four TSA derivatives designed and synthesized by our research group. The protective activity against hypoxia-reoxygenation injury in cells was evaluated, and derivative Ⅰ-3 was selected for in vivo experiments to verify its myocardial protective activity in rats with myocardial infarction. The results demonstrated that these four compounds could protect neonatal rat cardiomyocytes from hypoxia-reoxygenation injury. Among the derivatives, Ⅰ-3 showing superior protective effects, we found that Ⅰ-3 has enhanced metabolic stability and an extended half-life. Ⅰ-3 exhibited superior biological activity, effectively reducing the heart infarction area, alleviating myocardial hypertrophy, and enhancing cardiac pumping function. Ⅰ-3 reported in the present work represents a novel and effective derivative of TSA, showing great potential for the treatment of myocardial ischemia (MI).

Keywords

Salvia miltiorrhiza - Lamiaceae - Tanshinone ⅡA - derivatives - myocardial ischemia - coronary artery ligation - cardiomyocytes - hemodynamic

Publication History

Received: 23 October 2024

Accepted after revision: 24 March 2025

Accepted Manuscript online:
24 March 2025

Article published online:
25 April 2025

• References

• 1 WHO. World Health Statistics 2024: Monitoring Health for the SDGs, Sustainable Development Goals. Geneva: World Health Organization; 2024. Licence: CC BY-NC-SA 3.0 IGO
• 2 Writing committee of the report on cardiovascular health and diseases in China. Report on cardiovascular health and diseases in China 2021: An updated summary. Biomed Environ Sci 2022; 35: 573-603
• 3 Richard Conti C. Myocardial ischemia is not always due to epicardial atheromatous disease. Clin Cardiol 2011; 34: 8-9
• 4 Fioranelli M, Bottaccioli AG, Bottaccioli F, Bianchi M, Rovesti M, Roccia MG. Stress and inflammation in coronary artery disease: A review psychoneuroendocrineimmunology-based. Front Immunol 2018; 9: 2031
• 5 Wang L, Ma R, Liu C, Liu H, Zhu R, Guo S, Tang M, Li Y, Niu J, Fu M, Gao S, Zhang D. Salvia miltiorrhiza: A potential red light to the development of cardiovascular diseases. Curr Pharm Des 2017; 23: 1077-1097
• 6 Zeng J, Gao WW, Yang H, Wang YN, Mei Y, Liu TT, Wang M, Tang L, Ma DC, Li W. Sodium tanshinone IIA sulfonate suppresses microglia polarization and neuroinflammation possibly via regulating miR-125b-5 p/STAT3 axis to ameliorate neuropathic pain. Eur J Pharmacol 2024; 972: 176523
• 7 Subedi L, Gaire BP. Tanshinone IIA: A phytochemical as a promising drug candidate for neurodegenerative diseases. Pharmacol Res 2021; 169: 105661
• 8 Ma HH, Wan C, Zhang LD, Zhang RR, Peng D, Qiao LJ, Zhang SJ, Cai YF, Huang HQ. Sodium tanshinone IIA sulfonate improves cognitive impairment via regulating Aβ transportation in AD transgenic mouse model. Metab Brain Dis 2022; 37: 989-1001
• 9 Zhang YZ, Lai HL, Huang C, Jiang ZB, Yan HX, Wang XR, Xie C, Huang JM, Ren WK, Li JX, Zhai ZR, Yao XJ, Wu QB, Leung EL. Tanshinone IIA induces ER stress and JNK activation to inhibit tumor growth and enhance anti-PD-1 immunotherapy in non-small cell lung cancer. Phytomedicine 2024; 128: 155431
• 10 Jiang Y, Bi Y, Zhou L, Zheng S, Jian T, Chen J. Tanshinone IIA inhibits proliferation and migration by downregulation of the PI3K/Akt pathway in small cell lung cancer cells. BMC Complement Med Ther 2024; 24: 68
• 11 Hu T, Zou HX, Le SY, Wang YR, Qiao YM, Yuan Y, Liu JC, Lai SQ, Huang H. Tanshinone IIA confers protection against myocardial ischemia/reperfusion injury by inhibiting ferroptosis and apoptosis via VDAC1. Int J Mol Med 2023; 52: 109
• 12 Qian Y, He Y, Qiong A, Zhang W. Tanshinone IIA regulates MAPK/mTOR signal-mediated autophagy to alleviate atherosclerosis through the miR-214-3 p/ATG16L1 Axis. Int Heart J 2023; 64: 945-954
• 13 Jung I, Kim H, Moon S, Lee H, Kim B. Overview of Salvia miltiorrhiza as a potential therapeutic agent for various diseases: An update on efficacy and mechanisms of action. Antioxidants (Basel) 2020; 9: 857
• 14 Li ZM, Xu SW, Liu PQ. Salvia miltiorrhiza Burge (Danshen): A golden herbal medicine in cardiovascular therapeutics. Acta Pharmacol Sin 2018; 39 (05) 802-824
• 15 Fu J, Huang H, Liu J, Pi R, Chen J, Liu P. Tanshinone IIA protects cardiac myocytes against oxidative stress-triggered damage and apoptosis. Eur J Pharmacol 2007; 568: 213-221
• 16 Gao J, Yang G, Pi R, Li R, Wang P, Zhang H, Le K, Chen S, Liu P. Tanshinone IIA protects neonatal rat cardiomyocytes from adriamycin-induced apoptosis. Transl Res 2008; 151: 79-87
• 17 Pan C, Lou L, Huo Y, Singh G, Chen M, Zhang D, Wu A, Zhao M, Wang S, Li J. Salvianolic acid B and tanshinone IIA attenuate myocardial ischemia injury in mice by NO production through multiple pathways. Ther Adv Cardiovasc Dis 2011; 5: 99-111
• 18 Chan P, Liu JC, Lin LJ, Chen PY, Cheng TH, Lin JG, Hong HJ. Tanshinone IIA inhibits angiotensin II-induced cell proliferation in rat cardiac fibroblasts. Am J Chin Med 2011; 39: 381-394
• 19 Andersen ND, Ramachandran KV, Bao MM, Kirby ML, Pitt GS, Hutson MR. Calcium signaling regulates ventricular hypertrophy during development independent of contraction or blood flow. J Mol Cell Cardiol 2015; 80: 1-9
• 20 Zhai X, Li C, Lenon GB, Xue CCL, Li W. Preparation and characterisation of solid dispersions of tanshinone IIA, cryptotanshinone and total tanshinones. Asian J Pharm Sci 2017; 12: 85-97
• 21 Hao H, Wang G, Cui N, Li J, Xie L, Ding Z. Pharmacokinetics, absorption and tissue distribution of tanshinone IIA solid dispersion. Planta Med 2006; 72: 1311-1317
• 22 Li QN, Huang ZP, Gu QL, Zhi ZE, Yang YH, He L, Chen KL, Wang JX. Synthesis and biological evaluation of novel tanshinone IIA derivatives for treating pain. Chin J Nat Med 2018; 16: 113-124
• 23 Wang M, Niu A, Gong Z, Xu Z, Li L, Li B, Wang J. PEG-amino acid-przewaquinone a conjugations: Synthesis, physicochemical properties and protective effect in a rat model of brain ischemia-reperfusion. Bioorg Med Chem Lett 2020; 30: 126780
• 24 Feng C, Fan X, Zhang C, Shi X. On the quantitative analysis of focal ischemic cerebral infarction by TTC staining. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi 2009; 26: 1363-1366
• 25 Li P, Wang GJ, Li J, Zhang Q, Liu X, Khlentzos A, Roberts MS. The prediction of the hepatic clearance of tanshinone IIA in rat liver subcellular fractions: Accuracy improvement. Curr Drug Metab 2008; 9: 39-45
• 26 Bi HC. The pharmacokinetic study of tanshinone ⅡA in rats and the involved mechanisms. [Dissertation]. Guangdong: Sun Yat-sen University; 2007
• 27 Lott JA, Stang JM. Serum enzymes and isoenzymes in the diagnosis and differential diagnosis of myocardial ischemia and necrosis. Clin Chem 1980; 26: 1241-1250
• 28 Bugge-Asperheim B, Kjekshus J. Left ventricular pressure and maximum rate of pressure rise as determinants of myocardial oxygen consumption during hemorrhagic hypotension in dogs. Acta Physiol Scand 1970; 78: 174-183