Combination of the ginsenosides Rb3 and Rb2 exerts protective effects against myocardial ischemia reperfusion injury in rats

Liu,Xiaomin; Jiang,Yichuan; Fu,Wenwen; Yu,Xiaofeng; Sui,Dayun

doi:10.3892/ijmm.2019.4414

Combination of the ginsenosides Rb3 and Rb2 exerts protective effects against myocardial ischemia reperfusion injury in rats

Authors:
- Xiaomin Liu
- Yichuan Jiang
- Wenwen Fu
- Xiaofeng Yu
- Dayun Sui
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Affiliations: Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
Published online on: November 29, 2019 https://doi.org/10.3892/ijmm.2019.4414
Pages: 519-531
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Ginsenoside Rb3 (G‑Rb3) has been demonstrated to alleviate myocardial ischemia reperfusion injury (MIRI); however, it is difficult to separate G‑Rb2 from its isomer G‑Rb3. The current study aimed to compare the cardioprotective effects of G‑Rb3 and the concomitant use of G‑Rb3 and G‑Rb2 (G‑Rb3/Rb2) on MIRI in rats. A rat model of MIRI was established by ligation of the left anterior descending coronary artery and the rats were randomly divided into five groups. Prior to MIRI, G‑Rb3/Rb2 (20 mg/kg), G‑Rb3 (20 mg/kg) and diltiazem (DLZ; 20 mg/kg, as a positive control) were orally administered to the rats once a day for 3 consecutive days. After 30 min of ischemia and 120 min of reperfusion, cardiac function, infarct size, cardiac marker enzymes, antioxidative parameters, inflammatory factors, histopathological changes, cardiomyocyte apoptosis, and B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X protein and caspase‑3 expression were determined using a multi‑channel physiological recording system, nitrotetrazolium blue chloride, biochemical kits, radioimmunoassay kits, hematoxylin and eosin, terminal deoxynucleotidyl‑transferase‑mediated dUTP nick end labeling assay, immunohistochemistry and reverse transcription‑quantitative PCR, respectively. The results indicated that treatment with G‑Rb3/Rb2 significantly protected rats against MIRI, as shown by improved cardiac function, reduced myocardial ischemic area, decreased serum activities of aspartate aminotransferase, lactate dehydrogenase and creatine kinase MB, decreased serum concentrations of interleukin‑6 and tumor necrosis factor‑α, decreased malondialdehyde concentration in myocardial tissues, increased activities of superoxide dismutase, glutathione peroxidase and catalase in myocardial tissues, reduced histopathological changes in myocardial tissues, reduced number of apoptotic cardiomyocytes, and changes in the expression levels of caspase‑3, Bcl‑2 and Bax. In addition, the effects of treatment with G‑Rb3/Rb2, G‑Rb3 or DLZ were equivalent. The protective effects of G‑Rb3/Rb2 on MIRI were similar to those of G‑Rb3 in terms of oxidative stress, inflammatory factors and inhibition of cardiomyocyte apoptosis. Therefore, G‑Rb3/Rb2 may be developed as a concomitant treatment for MIRI.

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1	Karimi M, Zare H, Bakhshian Nik A, Yazdani N, Hamrang M, Mohamed E, Sahandi Zangabad P, Moosavi Basri SM, Bakhtiari L and Hamblin MR: Nanotechnology in diagnosis and treatment of coronary artery disease. Nanomedicine (Lond). 11:513–530. 2016. View Article : Google Scholar
2	Krokhaleva Y and Vaseghi M: Update on prevention and treatment of sudden cardiac arrest. Trends Cardiovasc Med. 29:394–400. 2019. View Article : Google Scholar
3	Zhou H, Ma Q, Zhu P, Ren J, Reiter RJ and Chen Y: Protective role of melatonin in cardiac ischemia-reperfusion injury: From pathogenesis to targeted therapy. J Pineal Res. 64:2018. View Article : Google Scholar : PubMed/NCBI
4	Rude RE, Muller JE and Braunwald E: Efforts to limit the size of myocardial infarcts. Ann Intern Med. 95:736–761. 1981. View Article : Google Scholar : PubMed/NCBI
5	Hausenloy DJ and Yellon DM: Myocardial ischemia-reperfusion injury: A neglected therapeutic target. J Clin Invest. 123:92–100. 2013. View Article : Google Scholar : PubMed/NCBI
6	Nesher N, Zisman E, Wolf T, Sharony R, Bolotin G, David M, Uretzky G and Pizov R: Strict thermoregulation attenuates myocardial injury during coronary artery bypass graft surgery as reflected by reduced levels of cardiac-specific troponin I. Anesth Analg. 96:328–335, table of contents. 2003.PubMed/NCBI
7	Jo MS, Lee J, Kim SY, Kwon HJ, Lee HK, Park DJ and Kim Y: Comparison between creatine kinase MB, heart-type fatty acid-binding protein, and cardiac troponin T for detecting myocardial ischemic injury after cardiac surgery. Clin Chim Acta. 488:174–178. 2019. View Article : Google Scholar
8	Virmani R, Forman MB and Kolodgie FD: Myocardial reperfusion injury. Histopathological effects of perfluorochemical. Circulation. 81(3 Suppl): IV57–IV68. 1990.PubMed/NCBI
9	Hou H, Wang Y, Li Q, Li Z, Teng Y, Li J, Wang X, Chen J and Huang N: The role of RIP3 in cardiomyocyte necrosis induced by mitochondrial damage of myocardial ischemia-reperfusion. Acta Biochim Biophys Sin (Shanghai). 50:1131–1140. 2018.
10	Ibáñez B, Heusch G, Ovize M and Van de Werf F: Evolving therapies for myocardial ischemia/reperfusion injury. J Am Coll Cardiol. 65:1454–1471. 2015. View Article : Google Scholar : PubMed/NCBI
11	Yu L, Zhang W, Huang C, Liang Q, Bao H, Gong Z, Xu M, Wang Z, Wen M and Cheng X: FoxO4 promotes myocardial ischemia-reperfusion injury: The role of oxidative stress-induced apoptosis. Am J Transl Res. 10:2890–2900. 2018.PubMed/NCBI
12	Davidson SM, Ferdinandy P, Andreadou I, Bøtker HE, Heusch G, Ibáñez B, Ovize M, Schulz R, Yellon DM, Hausenloy DJ, et al: Multitarget strategies to reduce myocardial ischemia/reperfusion injury: JACC review topic of the week. J Am Coll Cardiol. 73:89–99. 2019. View Article : Google Scholar : PubMed/NCBI
13	Gottlieb RA, Burleson KO, Kloner RA, Babior BM and Engler RL: Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest. 94:1621–1628. 1994. View Article : Google Scholar : PubMed/NCBI
14	Liu S, Ai Q, Feng K, Li Y and Liu X: The cardioprotective effect of dihydromyricetin prevents ischemia-reperfusion-induced apoptosis in vivo and in vitro via the PI3K/Akt and HIF-1α signaling pathways. Apoptosis. 21:1366–1385. 2016. View Article : Google Scholar : PubMed/NCBI
15	Shu Z, Yang Y, Yang L, Jiang H, Yu X and Wang Y: Cardioprotective effects of dihydroquercetin against ischemia reperfusion injury by inhibiting oxidative stress and endoplasmic reticulum stress-induced apoptosis via the PI3K/Akt pathway. Food Funct. 10:203–215. 2019. View Article : Google Scholar
16	Mokhtari-Zaer A, Marefati N, Atkin SL, Butler AE and Sahebkar A: The protective role of curcumin in myocardial ischemia-reperfusion injury. J Cell Physiol. 234:214–222. 2018. View Article : Google Scholar : PubMed/NCBI
17	Sun J, Yu X, Huangpu H and Yao F: Ginsenoside Rb3 protects cardiomyocytes against hypoxia/reoxygenation injury via activating the antioxidation signaling pathway of PERK/Nrf2/HMOX1. Biomed Pharmacother. 109:254–261. 2019. View Article : Google Scholar
18	Liu K, Chen H, You QS, Ye Q, Wang F, Wang S, Zhang SL, Yu KJ and Lu Q: Curcumin attenuates myocardial ischemia-reperfusion injury. Oncotarget. 8:112051–112059. 2017. View Article : Google Scholar
19	Wang CZ, Wu JA, McEntee E and Yuan CS: Saponins composition in American ginseng leaf and berry assayed by high-performance liquid chromatography. J Agric Food Chem. 54:2261–2266. 2006. View Article : Google Scholar : PubMed/NCBI
20	Kim JH: Pharmacological and medical applications of Panax ginseng and ginsenosides: A review for use in cardiovascular diseases. J Ginseng Res. 42:264–269. 2018. View Article : Google Scholar : PubMed/NCBI
21	Bai L, Gao J, Wei F, Zhao J, Wang D and Wei J: Therapeutic potential of ginsenosides as an adjuvant treatment for diabetes. Front Pharmacol. 9:4232018. View Article : Google Scholar : PubMed/NCBI
22	Wan JB, Yang FQ, Li SP, Wang YT and Cui XM: Chemical characteristics for different parts of Panax notoginseng using pressurized liquid extraction and HPLC-ELSD. J Pharm Biomed Anal. 41:1596–1601. 2006. View Article : Google Scholar : PubMed/NCBI
23	Liu X, Jiang Y, Yu X, Fu W, Zhang H and Sui D: Ginsenoside-Rb3 protects the myocardium from ischemia-reperfusion injury via the inhibition of apoptosis in rats. Exp Ther Med. 8:1751–1756. 2014. View Article : Google Scholar : PubMed/NCBI
24	Jiang Y, Zhong GG, Chen L and Ma XY: Influences of ginsenosides Rb1, Rb2, and Rb3 on electric and contractile activities of normal and damaged cultured myocardiocytes. Zhongguo Yao Li Xue Bao. 13:403–406. 1992.PubMed/NCBI
25	Sui DY, Chen YP, Yu XF, Wang ZC, Qu SC and Ma XY: Application of composition containing ginsenoside-Rb3 and ginsenoside-Rb2 to treatment of heart and cerebral vascular diseases. CN2012104745480. filed. November 21–2012.
26	Moukarbel GV, Ayoub CM and Abchee AB: Pharmacological therapy for myocardial reperfusion injury. Curr Opin Pharmacol. 4:147–153. 2004. View Article : Google Scholar : PubMed/NCBI
27	Pizzetti G, Mailhac A, Li Volsi L, Di Marco F, Lu C, Margonato A and Chierchia SL: Beneficial effects of diltiazem during myocardial reperfusion: A randomized trial in acute myocardial infarction. Ital Heart J. 2:757–765. 2001.PubMed/NCBI
28	Herzog WR, Vogel RA, Schlossberg ML, Edenbaum LR, Scott HJ and Serebruany VL: Short-term low dose intracoronary diltiazem administered at the onset of reperfusion reduces myocardial infarct size. Int J Cardiol. 59:21–27. 1997. View Article : Google Scholar : PubMed/NCBI
29	Chen C, Chen W, Nong Z, Ma Y, Qiu S and Wu G: Cardioprotective effects of combined therapy with hyperbaric oxygen and diltiazem pretreatment on myocardial ischemia-reperfusion injury in rats. Cell Physiol Biochem. 38:2015–2029. 2016. View Article : Google Scholar : PubMed/NCBI
30	Shi Y, Han B, Yu X, Qu S and Sui D: Ginsenoside Rb3 ameliorates myocardial ischemia-reperfusion injury in rats. Pharm Biol. 49:900–906. 2011. View Article : Google Scholar : PubMed/NCBI
31	National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals: Guide for the Care and Use of Laboratory Animals. 8th edition. National Academies Press; Washington, DC: 2011
32	Cao Y, Li YK, Chen MQ and Yao KW: Research progress on preparation of rat models of acute myocardial infarction. Chin J Compat Med. 27:96–100. 2017.
33	Zhang H, Xu H, Xie H, Li F, Yu X and Sui D: Cardiovascular protective effects of IL-1 ra-Fc-IL-18BP on experimental myocardial infarction by inhibiting oxidative stress and inflammation in a rat model. Pharmazie. 69:769–774. 2014.
34	Dai S, Hong Y, Xu J, Lin Y, Si Q and Gu X: Ginsenoside Rb2 promotes glucose metabolism and attenuates fat accumulation via AKT-dependent mechanisms. Biomed Pharmacother. 100:93–100. 2018. View Article : Google Scholar : PubMed/NCBI
35	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
36	Maulik N, Yoshida T, Engelman RM, Deaton D, Flack JE III, Rousou JA and Das DK: Ischemic preconditioning attenuates apoptotic cell death associated with ischemia/reperfusion. Mol Cell Biochem. 186:139–145. 1998. View Article : Google Scholar : PubMed/NCBI
37	Animal Models of Human Diseases. EQ L: People's Medical Publishing House; China: pp. p1132008
38	Zeller A, Arras M, Jurd R and Rudolph U: Identification of a molecular target mediating the general anesthetic actions of pentobarbital. Mol Pharmacol. 71:852–859. 2007. View Article : Google Scholar
39	Archer DP, Samanani N and Roth SH: Small-dose pentobarbital enhances synaptic transmission in rat hippocampus. Anesth Analg. 93:1521–1525, table of contents. 2001. View Article : Google Scholar : PubMed/NCBI
40	Nassiri AA, Hakemi MS, Asadzadeh R, Faizei AM, Alatab S, Miri R and Yaseri M: Differences in cardiovascular disease risk factors associated with maximum and mean carotid intima-media thickness among hemodialysis patients. Iran J Kidney Dis. 6:203–208. 2012.PubMed/NCBI
41	Peng S, Wang Y, Zhou Y, Ma T, Wang Y, Li J, Huang F, Kou J, Qi L, Liu B and Liu K: Rare ginsenosides ameliorate lipid overload-induced myocardial insulin resistance via modulating metabolic flexibility. Phytomedicine. 58:1527452019. View Article : Google Scholar : PubMed/NCBI
42	Luo Y, Pan YZ, Zeng C, Li GL, Lei XM, Liu Z and Zhou SF: Altered serum creatine kinase level and cardiac function in ischemia-reperfusion injury during percutaneous coronary intervention. Med Sci Monit. 17:CR474–CR479. 2011. View Article : Google Scholar : PubMed/NCBI
43	Ryter SW, Kim HP, Hoetzel A, Park JW, Nakahira K, Wang X and Choi AM: Mechanisms of cell death in oxidative stress. Antioxid Redox Signal. 9:49–89. 2007. View Article : Google Scholar
44	Han SY, Li HX, Ma X, Zhang K, Ma ZZ and Tu PF: Protective effects of purified safflower extract on myocardial ischemia in vivo and in vitro. Phytomedicine. 16:694–702. 2009. View Article : Google Scholar : PubMed/NCBI
45	Zhai KF, Duan H, Khan GJ, Xu H, Han FK, Cao WG, Gao GZ, Shan LL and Wei ZJ: Salicin from Alangium Chinense ameliorates rheumatoid arthritis by modulating the Nrf2-HO-1-ROS pathways. J Agric Food Chem. 66:6073–6082. 2018. View Article : Google Scholar : PubMed/NCBI
46	Lyu M, Cui Y, Zhao T, Ning Z, Ren J, Jin X, Fan G and Zhu Y: Tnfrsf12a-mediated atherosclerosis signaling and inflammatory response as a common protection mechanism of shuxuening injection against both myocardial and cerebral ischemia-reperfusion injuries. Front Pharmacol. 9:3122018. View Article : Google Scholar :
47	Zhai KF, Duan H, Luo L, Cao WG, Han FK, Shan LL and Fang XM: Protective effects of paeonol on inflammatory response in IL-1β-induced human fibroblast-like synoviocytes and rheumatoid arthritis progression via modulating NF-κB pathway. Inflammopharmacology. Aug 10–2017.Epub ahead of print. View Article : Google Scholar
48	Sun N, Wang H and Wang L: Protective effects of ghrelin against oxidative stress, inducible nitric oxide synthase and inflammation in a mouse model of myocardial ischemia/reperfusion injury via the HMGB1 and TLR4/NF-κB pathway. Mol Med Rep. 14:2764–2770. 2016. View Article : Google Scholar : PubMed/NCBI
49	Saraste A, Pulkki K, Kallajoki M, Henriksen K, Parvinen M and Voipio-Pulkki LM: Apoptosis in human acute myocardial infarction. Circulation. 95:320–323. 1997. View Article : Google Scholar : PubMed/NCBI
50	Fliss H and Gattinger D: Apoptosis in ischemic and reperfused rat myocardium. Circ Res. 79:949–956. 1996. View Article : Google Scholar : PubMed/NCBI
51	Haunstetter A and Izumo S: Apoptosis: Basic mechanisms and implications for cardiovascular disease. Circ Res. 11:1111–1129. 1998. View Article : Google Scholar
52	Guo M, Chen K, Lv Z, Shao Y, Zhang W, Zhao X and Li C: Bcl-2 mediates coelomocytes apoptosis by suppressing cytochrome c release in Vibrio splendidus challenged Apostichopus japonicus. Dev Comp Immunol. 103:1035332019. View Article : Google Scholar : PubMed/NCBI
53	Zhai KF, Duan H, Chen Y, Khan GJ, Cao WG, Gao GZ, Shan LL and Wei ZJ: Apoptosis effects of imperatorin on synoviocytes in rheumatoid arthritis through mitochondrial/caspase-mediated pathways. Food Funct. 9:2070–2079. 2018. View Article : Google Scholar : PubMed/NCBI