Abstract
Aim:
Liguzinediol is a novel derivative of ligustrazine isolated from the traditional Chinese medicine Chuanxiong (Ligusticum wallichii Franch), and produces significant positive inotropic effect in isolated rat hearts. In this study we investigated the effects of liguzinediol on a rat model of heart failure.
Methods:
To induce heart failure, male SD rats were injected with doxorubicin (DOX, 2 mg/kg, ip) once a week for 4 weeks. Then the rats were administered with liguzinediol (5, 10, 20 mg·kg−1·d−1, po) for 2 weeks. Hemodynamic examination was conducted to evaluate heart function. Myocardial cell apoptosis was examined morphologically. The expression of related genes and proteins were analyzed using immunohistochemical staining and Western blot assays, respectively.
Results:
Oral administration of liguzinediol dose-dependently improved the heart function in DOX-treated rats. Electron microscopy revealed that liguzinediol (10 mg·kg−1·d−1) markedly attenuated DOX-induced injury of cardiomyocytes, and decreased the number of apoptotic bodies in cardiomyocytes. Furthermore, liguzinediol significantly decreased Bax protein level, and increased Bcl-2 protein level in cardiomyocytes of DOX-treated rats, led to an increase in the ratio of Bcl-2/Bax. Moreover, liguzinediol significantly decreased the expression of both cleaved caspase-3 and NF-κB in cardiomyocytes of DOX-treated rats. Administration of digitalis (0.0225 mg·kg−1·d−1) also markedly improved the heart function and the morphology of cardiomyocytes in DOX-treated rats.
Conclusion:
Liguzinediol improves the heart function and inhibits myocardial cell apoptosis in the rat model of heart failure, which is associated with regulating Bcl-2, Bax, caspase-3 and NF-κB expression.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Liu Z, Li W, Wen HM, Bian HM, Zhang J, Chen L, et al. Synthesis, biological evaluation, and pharmacokinetic study of novel liguzinediol prodrugs. Molecules 2013; 18: 4561–72.
Dou YZ, Teng H, Wang Q . Preparation, in vitro release and percutaneous penetration of ligustrazine hydrochloride transdermal delivery system. Chin J Pharm 2008; 39: 745–9.
Liu X, Liu H, Zeng Z, Zhou W, Liu J, He Z . Pharmacokinetics of ligustrazine ethosome patch in rats and anti-myocardial ischemia and anti-ischemic reperfusion injury effect. Int J Nanomed 2011; 6: 1391–8.
Li W, Chen L, Bian HM . Application of 2,5-dihydroxymethyl-3,6-dimethylphrazine and its derivates in pharmacy. U S Patent 8, 158, 630, 17 April 2012.
Chen L, Xu Y, Li W, Wu H, Luo Z, Li X, et al. The novel compound liguzinediol exerts positive inotropic effects in isolated rat heart via sarcoplasmic reticulum Ca2+ ATPase-dependent mechanism. Life Sci 2012; 91: 402–8.
Lloyd-Jones D, Adams R, Carnethon M, De SG, Ferguson TB, Flegal K, et al. Heart disease and stroke statistics–2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009; 119: 480–6.
Hu SS, Kong LZ, Gao RL, Zhu ML, Wang W, Wang YJ, et al. Outline of the report on cardiovascular disease in China, 2010. Biomed Environ Sci 2012; 25: 251–6.
British Heart Foundation. Coronary heart disease statistics. BHF, 2012. http://www.heartstats.org
British Heart Foundation. Heart health conditions: heart failure. BHF, 2013. http://www.bhf.org.uk
National Clinical Guideline Centre (UK). Chronic Heart Failure- National clinical guideline for diagnosis and management in primary and secondary care. Royal College of Physicians (UK); 2010.
Sun JB, Yu CN, Xu D . Ginseng aconite and its small complex prescription shenfu decoction inhibiting doxorubicin-induced cardiotoxicity in rats. Liaoning J Tradit Chin Med 2012; 4: 754–6.
Yuan Y, Wang X, Zeng Q, Wu HM, Qi YF, Tang CS . Effects of continuous intermedin infusion on blood pressure and hemodynamic function in spontaneously hypertensive rats. J Geriatr Cardiol 2012; 9: 17–27.
Working PK, Newman MS, Sullivan T, Yarrington J . Reduction of the cardiotoxicity of doxorubicin in rabbits and dogs by encapsulation in long-circulating, pegylated liposomes. J Pharmacol Exp Ther 2012; 289: 1128–33.
Lai Y, Wu HJ, Zheng SD, Wu DL . The hemodynamic effects on chronic heart failure rats with Shen Fu Tang. Jilin J Tradit Chin Med 2013; 33: 276–77.
Nakamura T, Ueda Y, Juan Y, Katsuda S, Takahashi H, Koh E . Fas-mediated apoptosis in adriamycin-induced cardiomyopathy in rats in vivo study. Circulation 2000; 102: 572–8.
Abd El-Gawad HM, El-Sawalhi MM . Nitric oxide and oxidative stress in brain and heart of normal rats treated with doxorubicin: role of aminoguanidine. J Biochem Mol Toxicol 2004; 18: 69–77.
Perez GI, Robles R, Knudson CM, Flaws JA, Korsmeyer SJ, Tilly JL . Prolongation of ovarian life span into advanced chronological age by BAX-deficiency. Nat Genet 1999; 21: 200–3.
Tilly JL, Tilly KI, Kenton ML, Johnson AL . Expression of members of the bcl-2 gene family in the immature rat ovary: equine chorionic gonadotropin-mediated inhibition of granulosa cell apoptosis is associated with decreased bax and constitutive bcl-2 and bcl-xlong messenger ribonucleic acid levels. Endocrinology 1995; 136: 230–6.
Zhai P, Zeng J, Tan N, Wang J, Huang L, She W . Effects of vitamin C on A549 cell proliferation, apoptosis and expressions of caspase, survivin. China J Lung Cancer 2010; 2: 89–94.
Arlt A, Vorndamm J, Breitenbroich M, Folsch UR, Kalthoff H, Schmidt WE, et al. Inhibition of NF-κB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin. Oncogene 2001; 20: 859–68.
Somerville L, Cory JG . Enhanced roscovitine-induced apoptosis is mediated by a caspase-3-like activity in deoxyadenosine-resistant mouse leukemia L1210 cells. Anticancer Res 2000; 20: 3347–55.
Manna SK, Aggarwal BB . Lipopolysaccharide inhibits TNF-induced apoptosis: role of nuclear factor-κB activation and reactive oxygen intermediates. J Immunol 1999; 162: 1510–8.
Wang S, Kotamraju S, Konorev E, Kalivendi S, Joseph J, Kalyanaraman B . Activation of nuclear factor-kappaB during doxorubicin-induced apoptosis in endothelial cells and myocytes is pro-apoptotic: the role of hydrogen peroxide. Biochem J 2002; 367: 729–40.
Hsu SC, Gavrilin MA, Lee HH, Wu CC, Han SH, Lai MZ . NF-κB-dependent Fas ligand expression. Eur J Immunol 1999; 29: 2948–56.
Chan H, Bartos DP, Owen-Schaub LB . Activation-dependent transcriptional regulation of the human Fas promoter requires NF-κB p50/p65 recruitment. Mol Cell Biol 1999; 19: 2098–108.
Qin ZH, Chen RW, Wang Y, Nakai M, Chuang DM, Chase TN . Nuclear factor κB nuclear translocation upregulates c-Myc and p53 expression during NMDA receptor-mediated apoptosis in rat striatum. J Neurosci 1999; 19: 4023–33.
Hettmann T, DiDonato J, Karin M, Leiden JM . An essential role for nuclear factor-κB in promoting double positive thymocyte apoptosis. J Exp Med 1999; 189: 145–58.
Acknowledgements
This study is supported by the National Natural Science Foundation of China (No 81072542), the Natural Science Foundation of Jiangsu Province (No BK2011077), and the Research Fund for the Doctoral Program of Higher Education (No 20123237110010), as well as the College Student's Innovative Training Program, located in Jiangsu Province.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Li, Y., Song, P., Zhu, Q. et al. Liguzinediol improved the heart function and inhibited myocardial cell apoptosis in rats with heart failure. Acta Pharmacol Sin 35, 1257–1264 (2014). https://doi.org/10.1038/aps.2014.75
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/aps.2014.75
Keywords
This article is cited by
-
TAT-modified serum albumin nanoparticles for sustained-release of tetramethylpyrazine and improved targeting to spinal cord injury
Journal of Nanobiotechnology (2021)
-
The protective effects of liguzinediol on congestive heart failure induced by myocardial infarction and its relative mechanism
Chinese Medicine (2020)
-
Cardioprotective effects of garcinol following myocardial infarction in rats with isoproterenol-induced heart failure
AMB Express (2020)
-
Renal denervation improves cardiac function by attenuating myocardiocyte apoptosis in dogs after myocardial infarction
BMC Cardiovascular Disorders (2018)
-
Pretreatment with a combination of ligustrazine and berberine improves cardiac function in rats with coronary microembolization
Acta Pharmacologica Sinica (2016)
