Isosteviol: a potential cardioprotective agent

  • Aleksandar Jovanović University of Nicosia Medical School, Center for Neuroscience and Integrative Brain Research (CENIBRE), Department of Basic and Clinical Sciences
Keywords: cardioprotection, isosteviol

Abstract


Cardioprotection is a term describing the myocardial property to protect itself from injury, particularly in the context of ischemia-reperfusion injury and other metabolic stresses. Recently, isosteviol, a diterpene derived from the hydrolysis of stevioside, a natural sweetener found in the leaves of the Stevia rebaudiana plant, has emerged as a potential cardioprotective compound. In addition to the many therapeutic benefits of isosteviol, including antihyperglycemic, antihypertensive, and anti-inflammatory effects, recent studies have suggested that this compound might have cardioprotective properties as well. It has been demonstrated that isosteviol possesses antioxidant and anti-inflammatory activities, while also regulating ion channels and mitochondrial activity. The cardioprotective effects of isosteviol are mediated through its interaction with multiple signaling pathways. Pre-clinical work has demonstrated that isosteviol regulates NF-κB, phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathways, and adenosine monophosphate-activated protein kinase (AMPK), all of which are well-established cardioprotective signaling pathways. All these findings highlight isosteviol's potential as a cardioprotective therapeutic agent. However, this potential needs to be further tested in randomized controlled trials, along with examining isosteviol's possible value in clinical practice, defining optimal dosing strategies, and understanding its long-term effects.

References

Orellana-Paucar AM. Steviol glycosides from Stevia rebaudiana: An updated overview of their sweetening activity, pharmacological properties, and safety aspects. Molecules. 2023;28:1258.

Xu D, Li Y, Wang J, Davey AK, Zhang S, Evans AM. The cardioprotective effect of isosteviol on rats with heart ischemia-reperfusion injury. Life Sci. 2007;80:269-274.

Cao Y, Lu Z, Wang D, Tan KS, Liu W, Wu Q, et al. Therapeutic evaluation and metabolic reprograming of isosteviol sodium in a rat model of ischemic cardiomyopathy. Eur J Pharmacol. 2021;911:174539.

Jin H, Gerber JP, Wang J, Ji M, Davey AK. Oral and i.v. pharmacokinetics of isosteviol in rats as assessed by a new sensitive LC-MS/MS method. J Pharm Biomed Anal. 2008;48:986-990.

Adehin A, Tan KS, Lu Z, Cheng Q, Tan W. In vitro metabolic stability and biotransformation of isosteviol in human and rat liver fractions. Drug Metab Pharmacokinet. 2019;34:194-200.

Adehin A, Tan KS, Zou C, Lu Z, Lin Y, Wang D, et al. A compartmental approach to isosteviol's disposition in Sprague-Dawley rats. Naunyn Schmiedebergs Arch Pharmacol. 2020;393:1003-1011.

Chen Y, Beng H, Su H, Han F, Fan Z, Lv N, Jovanović A, Tan W. Isosteviol prevents the development of isoprenaline-induced myocardial hypertrophy. Int J Mol Med. 2019;44:1932-1942.

Zhang X, Lu Z, Abdul KSM, Changping MA, Tan KS, Jovanović A, Tan W. Isosteviol sodium protects heart embryonic H9c2 cells against oxidative stress by activating Akt/GSK-3β signaling pathway. Pharmazie. 2020;75:36-40.

Mei Y, Liu B, Su H, Zhang H, Liu F, Ke Q, et al. Isosteviol sodium protects the cardiomyocyte response associated with the SIRT1/PGC-1α pathway. J Cell Mol Med. 2020;24:10866-10875.

Abdul KSM, Faiz N, Jovanović A, Tan W. Isosteviol protects H9c2 cells against hypoxia-reoxygenation by activating ERK1/2. Cardiovasc Hematol Disord Drug Targets. 2021;21:73-77.

Jayachandra R, Zhao H, Cheng Z, Luo L, Sun T, Tan W. Synthesis of Isosteviol analogues as potential protective agents against Doxorubicin-induced cardiomyopathy in zebrafish embryos. Bioorg Med Chem Lett. 2019;29:1705-1709.

Mohammed Abdul KS, Rayadurgam J, Faiz N, Jovanović A, Tan W. Cardioprotection by isosteviol derivate JC105: A unique drug property to activate ERK1/2 only when cells are exposed to hypoxia-reoxygenation. J Cell Mol Med. 2020;24:10924-10934.

Zhang H, Liu B, Xu G, Xu C, Ou E, Liu J, et al. Synthesis and in vivo screening of isosteviol derivatives as new cardioprotective agents. Eur J Med Chem. 2021;219:113396.

Chen Z, Xu R, Jia Q, Xu X, Li D, Li Z, et al. Discovery of new D-ring modified isosteviol derivatives as potent cardioprotective agents against oxidative stress-trigged damage. Chem Biodivers. 2023;20:e202300085.

Chen Z, Li Z, Xu R, Xie Y, Li D, Zhao Y. Design, synthesis, and in vivo evaluation of isosteviol derivatives as new SIRT3 activators with highly potent cardioprotective effects. J Med Chem. 2024;67:6749-6768.

Sun X, Yang Y, Xie Y, Shi X, Huang L, Tan W. Protective role of STVNa in myocardial ischemia reperfusion injury by inhibiting mitochondrial fission. Oncotarget. 2017;9:1898-1905.

Fan Z, Wen T, Chen Y, Huang L, Lin W, Yin C, Tan W. Isosteviol sensitizes sarcKATP channels towards pinacidil and potentiates mitochondrial uncoupling of diazoxide in guinea pig ventricular myocytes. Oxid Med Cell Longev. 2016;2016:6362812.

Yin C, Chen Y, Wu H, Xu D, Tan W. Attenuation of ischemia/reperfusion-induced inhibition of the rapid component of delayed rectifier potassium current by isosteviol through scavenging reactive oxygen species. Biochim Biophys Acta Biomembr. 2017;1859:2447-2453.

Jovanović A. Cardioprotective signalling: Past, present and future. Eur J Pharmacol. 2018;833:314-319.

Sukhodub A, Jovanović S, Du Q, Budas G, Clelland AK, Shen M, et al. AMP-activated protein kinase mediates preconditioning in cardiomyocytes by regulating activity and trafficking of sarcolemmal ATP-sensitive K(+) channels. J Cell Physiol. 2007;210:224-236.

Mohammed Abdul KS, Jovanović S, Sukhodub A, Du Q, Jovanović A. Upregulation of cardioprotective SUR2A by sub-hypoxic drop in oxygen. Biochim Biophys Acta. 2014;1843:2424-2431.

Mohammed Abdul KS, Jovanović S, Jovanović A. Exposure to 15% oxygen in vivo up-regulates cardioprotective SUR2A without affecting ERK1/2 and AKT: a crucial role for AMPK. J Cell Mol Med. 2017;21:1342-1350.

Raghavan G, Bapna A, Mehta A, Shah A, Vyas T. Effect of sugar replacement with stevia-based tabletop sweetener on weight and cardiometabolic health among Indian adults. Nutrients. 2023;15:1744.

Published
2024/10/27
Section
Review articles