Oxidative stress suppression by luteolin-induced heme oxygenase-1 expression.
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(2)O(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(2)O(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.
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 & Peking Union Medical College, Beijing, 100193, PR China.
Gui-bo
GB
Sun
Xiao
X
Sun
Min
M
Wang
Jing-xue
JX
Ye
Jian-yong
JY
Si
Hui-bo
HB
Xu
Xiang-bao
XB
Meng
Meng
M
Qin
Jing
J
Sun
Hong-wei
HW
Wang
Xiao-bo
XB
Sun
D000818:Animals; D061745:Antioxidant Response Elements / Q000502:physiology; D001219:Aspartate Aminotransferases / Q000097:blood; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003402:Creatine Kinase / Q000097:blood; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D007770:L-Lactate Dehydrogenase / Q000097:blood; D047311:Luteolin / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D047428:Protein Kinase Inhibitors; D007770:L-Lactate Dehydrogenase; D051547:Heme Oxygenase-1; D001219:Aspartate Aminotransferases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D003402:Creatine Kinase; D047311:Luteolin