AccScience Publishing / GPD / Volume 2 / Issue 2 / DOI: 10.36922/gpd.387

Effect of Dunaliella salina on myocardial ischemia-reperfusion injury through KEAP1/NRF2 pathway activation and JAK2/STAT3 pathway inhibition

Jingjing Song1† Hongchao Li1† Yiru Zhang1 Tingting Wang1 Yibo Dong1 Hanqi Shui1 Jingxia Du1*
Show Less
1 School of Basic Medical, Henan University of Science and Technology, 263, Kaiyuan Avenue, Luoyang 471023, China
Submitted: 20 February 2023 | Accepted: 13 April 2023 | Published: 26 April 2023
© 2023 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( )

Myocardial ischemia-reperfusion injury (MIRI) is a life-threatening vascular emergency, in which oxidative stress and excessive inflammation reactions play significant roles. Dunaliella salina is rich in natural beta (β)-carotene, which is considered an antioxidant and anti-cancer compound, preventing night blindness, delaying aging, and regulating immunity. Due to its unique nutritional and functional components, D. salina has the potential to be developed as a nutritional health food. At present, it is unknown whether D. salina can rescue MIRI. The present study aimed at investigating whether D. salina has protective effect on MIRI and at exploring its potential mechanism. We developed a Langendorff perfused heart model in mice. The mice were given D. salina by gavage at a dose of 500 mg/kg for 7 days consecutively. It was found that D. salina could improve left ventricle function and reduce the rate of malignant arrhythmia and infarct size (P < 0.01). Furthermore, D. salina administration increased superoxide dismutase and decreased malondialdehyde content in myocardial tissue (P < 0.01). Importantly, real-time polymerase chain reaction and Western blot results showed that D. salina caused nuclear factor (erythroid-derived 2)-like 2 (NRF2) activation and enhanced the expression of antioxidative genes, such as heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1) (P < 0.05 and P < 0.01, respectively). At the same time, the phosphorylation of Janus kinase (JAK) and signal transducer and activator of transcription 3 (STAT3) was inhibited (P < 0.05 and P < 0.01, respectively), and proinflammatory cytokines interleukin-1 beta (IL-1β) and IL-6 decreased with D. salina administration (P < 0.05). In conclusion, D. salina has a protective effect on MIRI, which may be mediated by promoting kelch-like ECH-associated protein 1 (KEAP1)/NRF2 pathway and inhibiting JAK2/STAT3 signaling pathway.

Dunaliella salina
Myocardial ischemia-reperfusion injury
Henan Province Scientific and Technology Research Project
  1. Kwon SP, Hwang BH, Park EH, et al., 2021, Nanoparticle-mediated blocking of excessive inflammation for prevention of heart failure following myocardial infarction. Small, 17: e2101207.


  1. Wang J, Chen Z, Dai Q, et al., 2020, Intravenously delivered mesenchymal stem cells prevent microvascular obstruction formation after myocardial ischemia/reperfusion injury. Basic Res Cardiol, 115: 40.


  1. Lieder HR, Braczko F, Gedik N, et al., 2021, Cardioprotection by post-conditioning with exogenous triiodothyronine in isolated perfused rat hearts and isolated adult rat cardiomyocytes. Basic Res Cardiol, 116: 27.


  1. Yadid M, Lind JU, Ardoña HAM, et al., 2020, Endothelial extracellular vesicles contain protective proteins and rescue ischemia-reperfusion injury in a human heart-on-chip. Sci Transl Med, 12: eaax8005.


  1. Xu M, Li X, Song L, 2020, Baicalin regulates macrophages polarization and alleviates myocardial ischaemia/ reperfusion injury via inhibiting JAK/STAT pathway. Pharm Biol, 58: 655–663.


  1. Ucar BU, Ucar G, Saha S, et al., 2021, Pharmacological protection against ischemia-reperfusion injury by regulating the Nrf2-Keap1-ARE signaling pathway. Antioxidants (Basel), 10: 823.


  1. Sugamura K, Keaney JF Jr., 2011, Reactive oxygen species in cardiovascular disease. Free Radic Biol Med, 51: 978–992.


  1. El-Baz F, Aly HF, Abd-Alla HI, 2020, The ameliorating effect of carotenoid rich fraction extracted from Dunaliella salina microalga against inflammation-associated cardiac dysfunction in obese rats. Toxicol Rep, 7: 118–124.


  1. Madkour FF, Abdel-Daim MM, 2013, Hepatoprotective and antioxidant activity of Dunaliella salina in paracetamol-induced acute toxicity in rats. Indian J Pharm Sci, 75: 642–648.


  1. El-Baz F, Jaleel GAA, Saleh DO, et al., 2018, Protective and therapeutic potentials of Dunaliella salina on aging-associated cardiac dysfunction in rats. Asian Pac J Trop Bio, 8: 403–410.


  1. Li J, Ichikawa T, Villacorta L, et al., 2009, Nrf2 protects against maladaptive cardiac responses to hemodynamic stress. Arterioscler Thromb Vasc Biol, 29: 1843–1850.


  1. El-Baz FK, Elgohary R, Salama A, 2021, Amelioration of hepatic encephalopathy using Dunaliella salina microalgae in rats: Modulation of hyperammonemia/TLR4. Biomed Res Int, 2021: 8843218.


  1. Younis NS, Abduldaium MS, Mohamed ME, 2020, Protective effect of geraniol on oxidative, inflammatory and apoptotic alterations in isoproterenol-induced cardiotoxicity: Role of the Keap1/Nrf2/HO-1 and PI3K/Akt/mTOR pathways. Antioxidants (Basel), 9: 977.


  1. Zheng Y, Lu H, Huang H, 2020, Desflurane preconditioning protects against renal ischemia-reperfusion injury and inhibits inflammation and oxidative stress in rats through regulating the Nrf2-Keap1-ARE signaling pathway. Drug Des Devel Ther, 14: 1351–1362.


  1. Fang X, Liu Y, Lu J, et al., 2018, Protocatechuic aldehyde protects against isoproterenol-induced cardiac hypertrophy via inhibition of the JAK2/STAT3 signaling pathway. Naunyn Schmiedebergs Arch Pharmacol, 391: 1373–1385.


  1. Song M, Cui X, Zhang J, et al., 2022, Shenlian extract attenuates myocardial ischaemia-reperfusion injury via inhibiting M1 macrophage polarization by silencing miR- 155. Pharm Biol, 60: 2011–2024.


  1. Zhang WY, Zhang QL, Xu MJ, 2019, Effects of propofol on myocardial ischemia reperfusion injury through inhibiting the JAK/STAT pathway. Eur Rev Med Pharmacol Sci, 23: 6339–6345.


  1. Clark JD, Gebhart GF, Gonder JC, et al., 1997, Special report: The 1996 guide for the care and use of laboratory animals. ILAR J, 38: 41–48.


  1. Zhang J, Huang L, Shi X, et al., 2020, Metformin protects against myocardial ischemia-reperfusion injury and cell pyroptosis via AMPK/NLRP3 inflammasome pathway. Aging (Albany NY), 12: 24270–24287.


  1. Brewster LM, Haan YC, Zwinderman AH, et al., 2020, CK (creatine kinase) is associated with cardiovascular hemodynamics: The HELIUS study. Hypertension, 76: 3 73–380.


  1. Suwanjang W, Abramov AY, Charngkaew K, et al., 2016, Melatonin prevents cytosolic calcium overload, mitochondrial damage and cell death due to toxically high doses of dexamethasone-induced oxidative stress in human neuroblastoma SH-SY5Y cells. Neurochem Int, 97: 34–41.


  1. Takayanagi R, Inoguchi T, Ohnaka K, 2011, Clinical and experimental evidence for oxidative stress as an exacerbating factor of diabetes mellitus. J Clin Biochem Nutr, 48: 72–77.


  1. Zhou Q, Song J, Wang Y, et al., 2020, Remifentanil attenuates cardiac dysfunction, lipid peroxidation and immune disorder in rats with isoproterenol-induced myocardial injury via JNK/NF-KB p65 inhibition. Ann Transl Med, 8: 551.


  1. Guleken Z, Kuruca SE, Ünübol B, et al., 2020, Biochemical assay and spectroscopic analysis of oxidative/antioxidative parameters in the blood and serum of substance use disorders patients. A methodological comparison study. Spectrochim Acta A Mol Biomol Spectrosc, 240: 118625.


  1. Kong L, Deng J, Zhou X, et al., 2021, Sitagliptin activates the p62-Keap1-Nrf2 signalling pathway to alleviate oxidative stress and excessive autophagy in severe acute pancreatitis-related acute lung injury. Cell Death Dis, 12: 928.


  1. Shaw P, Chattopadhyay A, 2020, Nrf2-ARE signaling in cellular protection: Mechanism of action and the regulatory mechanisms. J Cell Physiol, 235: 3119–3130.


  1. Gañán-Gómez I, Wei Y, Yang H, et al., 2013, Oncogenic functions of the transcription factor Nrf2. Free Radic Biol Med, 65: 750–764.


  1. Zhang Z, Peng L, Fu Y, et al., 2021, Ginnalin A binds to the subpockets of keap1 Kelch domain to activate the Nrf2- regulated antioxidant defense system in SH-SY5Y cells. ACS Chem Neurosci, 12: 872–882.


  1. Geng Z, Fan WY, Zhou B, et al., 2019, FNDC5 attenuates obesity-induced cardiac hypertrophy by inactivating JAK2/ STAT3-associated inflammation and oxidative stress. J Transl Med, 17: 107.


  1. Liu X, Ye L, Bai Y, et al., 2008, Activation of the JAK/STAT-1 signaling pathway by IFN-gamma can down-regulate functional expression of the MHC class I-related neonatal Fc receptor for IgG. J Immunol, 181: 449–463.


  1. Zhang M, Wang X, Wang X, et al., 2013, Oxymatrine protects against myocardial injury via inhibition of JAK2/STAT3 signaling in rat septic shock. Mol Med Rep, 7: 1293–1299.
Conflict of interest
The authors declare that they have no competing interests.
Back to top
Gene & Protein in Disease, Electronic ISSN: 2811-003X Published by AccScience Publishing