Download PDF
Planta Med 2024; 90(11): 885-895
DOI: 10.1055/a-2341-6175
Biological and Pharmacological Activity
Original Papers

5(S)-5-Carboxystrictosidine from the Root of Mappianthus iodoides Ameliorates H2O2-induced Apoptosis in H9c2 Cardiomyocytes via PI3K/AKT and ERK Pathways

Ying Han‡
1   Department of Physiology, College of Chinese Medicine and Life Science, Jiangxi University of Chinese Medicine, Nanchang City, Jiangxi Province, China
5   Key Laboratory of Psychology of TCM and Brain Science, Jiangxi Administration of traditional Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang City, Jiangxi Province, China
,
Junli Xi‡
1   Department of Physiology, College of Chinese Medicine and Life Science, Jiangxi University of Chinese Medicine, Nanchang City, Jiangxi Province, China
,
Puzhao Zhang
2   Key Laboratory of Innovation Drug and Efficient Energy-saving Pharmaceutical Equipment, Jiangxi University of Chinese Medicine, Nanchang City, Jiangxi Province, China
,
Ming Gong
1   Department of Physiology, College of Chinese Medicine and Life Science, Jiangxi University of Chinese Medicine, Nanchang City, Jiangxi Province, China
,
Tao Luo
3   Blood Purification Center of the First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, China
,
Feng Shao
2   Key Laboratory of Innovation Drug and Efficient Energy-saving Pharmaceutical Equipment, Jiangxi University of Chinese Medicine, Nanchang City, Jiangxi Province, China
,
Yongxin Li
1   Department of Physiology, College of Chinese Medicine and Life Science, Jiangxi University of Chinese Medicine, Nanchang City, Jiangxi Province, China
,
Lingyun Zhong
4   College of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang City, Jiangxi Province, China
,
Hexiu Quan
1   Department of Physiology, College of Chinese Medicine and Life Science, Jiangxi University of Chinese Medicine, Nanchang City, Jiangxi Province, China
› Author AffiliationsSupported by: Top Discipline of Jiangxi Province，Discipline of Chinese and Western Integrative Medicine, Jiangxi University of Chinese Medicine zxyylxk20220103
Supported by: The Graduate Student Innovation special Fund Project of Jiangxi Province YC2021-S485
Supported by: Inherited and Innovative Group of Processing Technique of Traditional Chinese Medicine CXTD22003
Supported by: Science and Technology Project of Jiangxi Provincial Health Commission 202211410
Supported by: The Science and Technology Research Project of Jiangxi Provincial Department of Education, China GJJ2200958
Supported by: The Science and Technology Research Project of Jiangxi Provincial Department of Education, China GJJ211204
Supported by: Innovation and Entrepreneurship training program for college students in Jiangxi Province X202310412181
Supported by: Science and technology project of Jiangxi Provincial Administration of Traditional Chinese Medicine 2023B1182
› Further Information
Also available at
    Permissions and Reprints

Abstract

5(S)-5-carboxystrictosidine (5-CS) is a compound found in the root of Mappianthus iodoides, a traditional Chinese medicine used for the treatment of coronary artery disease. The aim of the present study was to investigate the protective effect of 5-CS against oxidative stress-induced apoptosis in H9c2 cardiomyocytes and the underlying mechanisms. 5-CS pretreatment significantly protected against H2O2-induced cell death, LDH leakage, and malondialdehyde (MDA) production, which are indicators for oxidative stress injury. 5-CS also enhanced the activity of SOD and CAT. In addition, 5-CS pretreatment significantly inhibited H2O2-induced apoptosis, as determined by flow cytometer, suppressed the activity of caspase-3 and caspase-9, and attenuated the activation of cleaved caspase-3 and caspase-9. 5-CS also increased Akt and ERK activation altered by H2O2 using Western blot analysis. The PI3K-specific inhibitor LY294002 abolished 5-CS-induced Akt activation. The ERK-specific inhibitor PD98059 abolished 5-CS-induced ERK activation. Both LY294002 and PD98059 attenuated the protective effect of 5-CS on H9c2 cardiomyocytes against H2O2-induced apoptosis and cell death. Taken together, these results demonstrate that 5-CS prevents H2O2-induced oxidative stress injury in H9c2 cells by enhancing the activity of the endogenous antioxidant enzymes, inhibiting apoptosis, and modulating PI3K/Akt and ERK signaling pathways.

Keywords

5(S)-5-carboxystrictosidine - Mappianthus iodoides - Icacinaceae - myocardial apoptosis - reactive oxygen species - PI3K/Akt - ERK

Supporting Information

    The extraction method of 5-CS from Mappianthus iodoides and the effects used in the Western blotting assay are described in the supplemental material.

  • Supporting Information


Publication History

Received: 14 November 2023

Accepted after revision: 10 June 2024

Accepted Manuscript online:
10 June 2024

Article published online:
19 July 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Cardiovascular Diseases. Available online (Accessed: February 1, 2024): https://www.who.int/health-topics/cardiovascular-diseases%23tab=tab_1
    PubMedGoogle Scholar
  • 2 Lee Y, Gustafsson AB. Role of apoptosis in cardiovascular disease. Apoptosis 2009; 14: 536-548
    CrossrefPubMedGoogle Scholar
  • 3 Haunstetter A, Izumo S. Apoptosis: Basic mechanisms and implications for cardiovascular disease. Circ Res 1998; 82: 1111-1129
    CrossrefPubMedGoogle Scholar
  • 4 Senoner T, Dichtl W. Oxidative stress in cardiovascular diseases: Still a therapeutic target?. Nutrients 2019; 11: 2090
    CrossrefPubMedGoogle Scholar
  • 5 Mikhed Y, Daiber A, Steven S. Mitochondrial oxidative stress, mitochondrial DNA damage and their role in age-related vascular dysfunction. Int J Mol Sci 2015; 16: 15918-15953
    CrossrefPubMedGoogle Scholar
  • 6 Sugamura K, Keaney JF. Reactive oxygen species in cardiovascular disease. Free Radic Biol Med 2011; 51: 978-992
    CrossrefPubMedGoogle Scholar
  • 7 Brown DI, Griendling KK. Regulation of signal transduction by reactive oxygen species in the cardiovascular system. Circ Res 2015; 116: 531-550
    CrossrefPubMedGoogle Scholar
  • 8 Droge W. Free radicals in the physiological control of cell function. Physiol Rev 2002; 82: 47-95
    CrossrefPubMedGoogle Scholar
  • 9 Cha X, Zhan WT. Chinese Materia Medica, Dai Medicine Rolls. Shanghai: Science and Technology Press; 2005: 165
    Google Scholar
  • 10 Patel H, Mishra R, Wier A, Mokhtarpour N, Merino EJ, Garrett JT. RIDR-PI-103, ROS-activated prodrug PI3K inhibitor inhibits cell growth and impairs the PI3K/Akt pathway in BRAF and MEK inhibitor-resistant BRAF-mutant melanoma cells. Anticancer Drugs 2023; 34: 519-531
    CrossrefPubMedGoogle Scholar
  • 11 Fan Z, Liu Y, Liu X, Nian W, Huang X, Yang Q, Hou S, Chen F. Phosphorylation of AKT by lysyl oxidase-like 2 activates the PI3K/AKT signaling pathway to promote proliferation, invasion and metastasis in esophageal squamous carcinoma. Clin Transl Oncol 2023; 25: 2487-2498
    CrossrefPubMedGoogle Scholar
  • 12 Dai W, Ni Z, Zhang G, Xu J, Qin X, Cao J, Liu L. JDHY3 inhibits hypopharyngeal carcinoma cell proliferation and promotes apoptosis by inhibiting the PI3K/AKT pathway. Anticancer Agents Med Chem 2023; 23: 1327-1335
    CrossrefPubMedGoogle Scholar
  • 13 Jiang X, Yin H, Su W, Quan H, Yuan X, Feng X, Li P, He Y, Xiao J, Li R. Trifolirhizin inhibits proliferation, migration and invasion in nasopharyngeal carcinoma cells via PI3K/Akt signaling pathway suppression. Biochem Biophys Res Commun 2023; 30: 111-119
    CrossrefPubMedGoogle Scholar
  • 14 Liu Q, Jin Z, Xu Z, Yang H, Li L, Li G, Li F, Gu S, Zong S, Zhou J. Antioxidant effects of ginkgolides and bilobalide against cerebral ischemia injury by activating the Akt/Nrf2 pathway in vitro and in vivo. Cell Stress Chaperones 2019; 24: 441-452
    CrossrefPubMedGoogle Scholar
  • 15 Samakova A, Gazova A, Sabova N, Valaskova S, Jurikova M, Kyselovic J. The pi3 k/Akt pathway is associated with angiogenesis, oxidative stress and survival of mesenchymal stem cells in pathophysiologic condition in ischemia. Physiol Res 2019; 68: S131
    CrossrefPubMedGoogle Scholar
  • 16 Amaravadi R, Thompson CB. The survival kinases Akt and Pim as potential pharmacological targets. J Clin Invest 2005; 115: 2618-2624
    CrossrefPubMedGoogle Scholar
  • 17 Turner NA, Xia F, Azhar G, Zhang X, Liu L, Wei JY. Oxidative stress induces DNA fragmentation and caspase activation via the c-Jun NH2-terminal kinase pathway in H9c2 cardiac muscle cells. J Mol Cell Cardiol 1998; 30: 1789-1801
    CrossrefPubMedGoogle Scholar
  • 18 Zhou X, Guo Y, Yang K, Liu P, Wang J. The signaling pathways of traditional Chinese medicine in promoting diabetic wound healing. J Ethnopharmacol 2022; 282: 114662
    CrossrefPubMedGoogle Scholar
  • 19 Hu P, Liu Y, Li S, Zhao Y, Gu H, Zong Q, Ahmed AA, Bao W, Liu HY, Cai D. Lactoferrin relieves deoxynivalenol-induced oxidative stress and inflammatory response by modulating the Nrf2/MAPK pathways in the liver. J Agric Food Chem 2023; 71: 8182-8191
    CrossrefPubMedGoogle Scholar
  • 20 Dhalla NS, Temsah RM, Netticadan T. Role of oxidative stress in cardiovascular diseases. J Hypertens 2000; 18: 655-673
    CrossrefPubMedGoogle Scholar
  • 21 Kevin LG, Novalija E, Stowe DF. Reactive oxygen species is mediators of cardiac injury and protection: The relevance to anesthesia practice. Anesth Analg 2005; 101: 1275-1287
    CrossrefPubMedGoogle Scholar
  • 22 Yin XL, Shen H, Zhang W, Yang Y. Inhibition of endoplasm reticulum stress by anisodamine protects against myocardial injury after cardiac arrest and resuscitation in rats. Am J Chin Med 2011; 39: 853-866
    CrossrefPubMedGoogle Scholar
  • 23 Lakshmi SV, Padmaja G, Kuppusamy P, Kutala VK. Oxidative stress in cardiovascular disease. Indian J Biochem Bio 2009; 46: 421-440
    PubMedGoogle Scholar
  • 24 Hong HJ, Liu JC, Cheng TH, Chan P. Tanshinone IIA attenuates angiotensin II-induced apoptosis via Akt pathway in neonatal rat cardiomyocytes. Acta Pharmacol Sin 2010; 31: 1569-1575
    CrossrefPubMedGoogle Scholar
  • 25 Xue CB, Liu W, Wu JH, Yang XL, Xu HB. Chemoprotective effect of N-acetylcysteine (NAC) on cellular oxidative damages and apoptosis induced by nano titanium dioxide under UVA irradiation. Toxicol In Vitro 2011; 25: 110-116
    CrossrefPubMedGoogle Scholar
  • 26 Zhang Q, Xiang J, Wang X, Liu H, Hu B, Feng M, Fu Q. Beta(2)-adrenoceptor agonist clenbuterol reduces infarct size and myocardial apoptosis after myocardial ischaemia/reperfusion in anaesthetized rats. Br J Pharmacol 2010; 160: 1561-1572
    CrossrefPubMedGoogle Scholar
  • 27 Franklin JL. Redox regulation of the intrinsic pathway in neuronal apoptosis. Antioxid Redox Signal 2011; 14: 1437-1448
    CrossrefPubMedGoogle Scholar
  • 28 Xia P, Liu Y, Cheng Z. Signaling pathways in cardiac myocyte apoptosis. Biomed Res Int 2016; 2016: 9583268
    PubMedGoogle Scholar
  • 29 Han Y, Li CF, Zhang PZ, Yang XQ, Min JX, Wu QH, Xie YY, Jin DZ, Wang ZT, Shao F, Quan HX. Protective effects of 5(S)-5-carboxystrictosidine on myocardial ischemia-reperfusion injury through activation of mitochondrial KATP channels. Eur J Pharmacol 2022; 920: 174811
    CrossrefPubMedGoogle Scholar
  • 30 Wang L, Lu Z, Zhao J, Schank M, Cao D, Dang X, Nguyen LN, Nguyen LNT, Khanal S, Zhang J, Wu XY, El Gazzar M, Ning S, Moorman JP, Yao ZQ. Selective oxidative stress induces dual damage to telomeres and mitochondria in human T cells. Aging Cell 2021; 20: e13513
    CrossrefPubMedGoogle Scholar
  • 31 Dhalla NS, Elmoselhi AB, Hata T, Makino N. Status of myocardial antioxidants in ischemia-reperfusion injury. Cardiovasc Res 2000; 47: 446-456
    CrossrefPubMedGoogle Scholar
  • 32 Zhang MQ, Zhang YL, Chen H, Tu JF, Shen Y, Guo JP, Yang XH, Yuan SR, Chen LZ, Chai JJ, Lu JH, Zhai CL. Sodium tanshinone IIA sulfonate protects rat myocardium against ischemia-reperfusion injury via activation of PI3K/Akt/FOXO3A/Bim pathway. Acta Pharmacol Sin 2013; 34: 1386-1396
    CrossrefPubMedGoogle Scholar
  • 33 Matsui T, Tao J, del Monte F, Lee KH, Li L, Picard M, Force TL, Franke TF, Hajjar RJ, Rosenzweig A. Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo. Circulation 2001; 104: 330-335
    CrossrefPubMedGoogle Scholar
  • 34 Zhao H, Sapolsky RM, Steinberg GK. Phosphoinositide-3-kinase/Akt survival pathways are implicated in neuronal survival after stroke. Mol Neurobiol 2006; 34: 249-270
    CrossrefPubMedGoogle Scholar
  • 35 Rose BA, Force T, Wang Y. Mitogen-activated protein kinase signaling in the heart: Angels versus demons in a heart-breaking tale. Physiol Rev 2010; 90: 1507-1546
    CrossrefPubMedGoogle Scholar
  • 36 Genestra M. Oxyl radicals, redox-sensitive signalling cascades and antioxidants. Cell Signal 2007; 19: 1807-1819
    CrossrefPubMedGoogle Scholar
  • 37 Zhang JY, Guo Y, Si JP, Sun XB, Sun GB, Liu JJ. A polysaccharide of Dendrobium officinale ameliorates H2O2-inducedapoptosis in H9c2 cardiomyocytes via PI3K/AKT and MAPK pathways. Int J Biol Macromol 2017; 104: 1-10
    CrossrefPubMedGoogle Scholar