Simvastatin inhibits lipopolysaccharide-induced tumor necrosis factor-alpha expression in neonatal rat cardiomyocytes: The role of reactive oxygen species.
Tumor necrosis factor-alpha (TNF-alpha) is implicated in heart failure and cardiomyocytes themselves can express TNF-alpha. Nevertheless, the mechanisms and regulations of TNF-alpha expression in cardiomyocytes remain poorly understood. The present study was to investigate the effects of simvastatin on TNF-alpha expression in cardiomyocytes and the underlying molecular mechanisms. In neonatal rat cardiomyocytes, RT-PCR and ELISA showed lipopolysaccharide (LPS)-induced TNF-alpha expression was attenuated by simvastatin pretreatment in a dose-dependent manner. The reactive oxygen species (ROS) scavenger N-acetylcysteine and the NADPH oxidase inhibitor diphenyleneiodonium also inhibited the LPS-induced expression of TNF-alpha. Dichlorofluorescein-fluorescence and cytochrome c reduction assay indicated LPS increased ROS generation and NADPH oxidase activity in cardiomyocytes, which were abrogated by simvastatin. Furthermore, similar to LPS, exogenous hydrogen peroxide also increased TNF-alpha secretion, but simvastatin did not significantly affect the hydrogen peroxide-induced TNF-alpha secretion. All the effects of simvastatin as mentioned above were completely reversed by concomitant pretreatment with mevalonate, a key intermediate during cholesterol synthesis. These results suggest that simvastatin attenuates LPS-induced TNF-alpha expression in cardiomyocytes via inhibition of activation of NADPH oxidase and subsequent ROS generation.
Shang
Fujun
F
Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, PR China.
Zhao
Lianyou
L
Zheng
Qiangsun
Q
Wang
Jiepin
J
Xu
Zhe
Z
Liang
Wenbing
W
Liu
Hui
H
Liu
Shaowei
S
Zhang
Lijuan
L
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D016166:Free Radical Scavengers / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors*; D009861:Onium Compounds / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019821:Simvastatin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D016166:Free Radical Scavengers; D000960:Hypolipidemic Agents; D008070:Lipopolysaccharides; D009861:Onium Compounds; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C007517:diphenyleneiodonium; D019821:Simvastatin; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D008798:Mevalonic Acid; D000111:Acetylcysteine