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Title: Oxidative stress suppression by luteolin-induced heme oxygenase-1 expression

Abstract

Luteolin, a flavonoid that exhibits antioxidative properties, exerts myocardial protection effects. However, the underlying molecular mechanisms are not yet fully understood. To investigate the effects of luteolin on myocardial injury protection and its possible mechanisms, a myocardial injury model was established with intragastric administration of 4 mg/kg isoproterenol (ISO) to male Sprague–Dawley rats (200–220 g) daily for 2 days. We found that pretreatment of luteolin (160, 80 and 40 mg/kg, i.g., respectively) daily for 15 days can prevent ISO-induced myocardial damage, including decrease of serum cardiac enzymes, improvement electrocardiography and heart vacuolation. Luteolin also improved the free radical scavenging and antioxidant potential, suggesting one possible mechanism of luteolin-induced cardio-protection is mediated by blocking the oxidative stress. To clarify the mechanisms, we performed the in vitro study by hydrogen peroxide (H{sub 2}O{sub 2})-induced cytotoxicty model in H9c2 cells. We found that luteolin pretreatment prevented apoptosis, increased the expression of heme oxygenase-1 (HO-1), and enhanced the binding of Nrf2 to the antioxidant response element, providing an adaptive survival response against H{sub 2}O{sub 2}-derived oxidative cytotoxicity. The addition of Znpp, a selective HO-1 competitive inhibitor, reduced the cytoprotective ability of luteolin, indicating the vital role of HO-1 on these effects. Luteolin also activatedmore » Akt and ERK, whereas the addition of LY294002 and U0126, the pharmacologic inhibitors of PI3K and ERK, attenuated luteolin-induced HO-1 expression and cytoprotective effect. Taken together, the above findings suggest that luteolin protects against myocardial injury and enhances cellular antioxidant defense capacity through the activation of Akt and ERK signal pathways that leads to Nrf2 activation, and subsequently HO-1 induction. -- Highlights: ► Luteolin prevents isoproterenol-induced myocardial damage. ► Luteolin enhances cellular antioxidant defense capacity. ► Luteolin increases the expression of heme oxygenase-1 protein levels. ► Luteolin activates Akt and ERK signal pathways.« less

Authors:
; ;  [1];  [2];  [1];  [3]; ; ;  [1];  [4];  [1]
  1. Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193 (China)
  2. Jilin Agricultural University, No.2888, Xincheng Street, Changchun, 130021, Jilin (China)
  3. Academy of Chinese Medical Sciences of Jilin Province, Gongnongda road 1745, Changchun, 130021, Jiblin (China)
  4. Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093 (China)
Publication Date:
OSTI Identifier:
22215993
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 265; Journal Issue: 2; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTIOXIDANTS; APOPTOSIS; ENZYMES; HEME; HYDROGEN PEROXIDE; IN VITRO; INHIBITION; INJURIES; OXIDATION; RATS; TOXICITY

Citation Formats

Sun, Gui-bo, Sun, Xiao, Wang, Min, Ye, Jing-xue, Si, Jian-yong, Xu, Hui-bo, Meng, Xiang-bao, Qin, Meng, Sun, Jing, Wang, Hong-wei, and Sun, Xiao-bo. Oxidative stress suppression by luteolin-induced heme oxygenase-1 expression. United States: N. p., 2012. Web. doi:10.1016/J.TAAP.2012.10.002.
Sun, Gui-bo, Sun, Xiao, Wang, Min, Ye, Jing-xue, Si, Jian-yong, Xu, Hui-bo, Meng, Xiang-bao, Qin, Meng, Sun, Jing, Wang, Hong-wei, & Sun, Xiao-bo. Oxidative stress suppression by luteolin-induced heme oxygenase-1 expression. United States. https://doi.org/10.1016/J.TAAP.2012.10.002
Sun, Gui-bo, Sun, Xiao, Wang, Min, Ye, Jing-xue, Si, Jian-yong, Xu, Hui-bo, Meng, Xiang-bao, Qin, Meng, Sun, Jing, Wang, Hong-wei, and Sun, Xiao-bo. 2012. "Oxidative stress suppression by luteolin-induced heme oxygenase-1 expression". United States. https://doi.org/10.1016/J.TAAP.2012.10.002.
@article{osti_22215993,
title = {Oxidative stress suppression by luteolin-induced heme oxygenase-1 expression},
author = {Sun, Gui-bo and Sun, Xiao and Wang, Min and Ye, Jing-xue and Si, Jian-yong and Xu, Hui-bo and Meng, Xiang-bao and Qin, Meng and Sun, Jing and Wang, Hong-wei and Sun, Xiao-bo},
abstractNote = {Luteolin, a flavonoid that exhibits antioxidative properties, exerts myocardial protection effects. However, the underlying molecular mechanisms are not yet fully understood. To investigate the effects of luteolin on myocardial injury protection and its possible mechanisms, a myocardial injury model was established with intragastric administration of 4 mg/kg isoproterenol (ISO) to male Sprague–Dawley rats (200–220 g) daily for 2 days. We found that pretreatment of luteolin (160, 80 and 40 mg/kg, i.g., respectively) daily for 15 days can prevent ISO-induced myocardial damage, including decrease of serum cardiac enzymes, improvement electrocardiography and heart vacuolation. Luteolin also improved the free radical scavenging and antioxidant potential, suggesting one possible mechanism of luteolin-induced cardio-protection is mediated by blocking the oxidative stress. To clarify the mechanisms, we performed the in vitro study by hydrogen peroxide (H{sub 2}O{sub 2})-induced cytotoxicty model in H9c2 cells. We found that luteolin pretreatment prevented apoptosis, increased the expression of heme oxygenase-1 (HO-1), and enhanced the binding of Nrf2 to the antioxidant response element, providing an adaptive survival response against H{sub 2}O{sub 2}-derived oxidative cytotoxicity. The addition of Znpp, a selective HO-1 competitive inhibitor, reduced the cytoprotective ability of luteolin, indicating the vital role of HO-1 on these effects. Luteolin also activated Akt and ERK, whereas the addition of LY294002 and U0126, the pharmacologic inhibitors of PI3K and ERK, attenuated luteolin-induced HO-1 expression and cytoprotective effect. Taken together, the above findings suggest that luteolin protects against myocardial injury and enhances cellular antioxidant defense capacity through the activation of Akt and ERK signal pathways that leads to Nrf2 activation, and subsequently HO-1 induction. -- Highlights: ► Luteolin prevents isoproterenol-induced myocardial damage. ► Luteolin enhances cellular antioxidant defense capacity. ► Luteolin increases the expression of heme oxygenase-1 protein levels. ► Luteolin activates Akt and ERK signal pathways.},
doi = {10.1016/J.TAAP.2012.10.002},
url = {https://www.osti.gov/biblio/22215993}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 2,
volume = 265,
place = {United States},
year = {Sat Dec 01 00:00:00 EST 2012},
month = {Sat Dec 01 00:00:00 EST 2012}
}