Time-dependent inhibitory effect of lipopolysaccharide injection on Per1 and Per2 gene expression in the mouse heart and liver.
Lipopolysaccharide (LPS) is a pathogen-associated large molecule responsible for sepsis-related endotoxic shock, and the heart is one of the most common organs adversely affected. LPS is reported to increase serum TNFalpha levels and reduce Per1 and Per2 gene expression. Therefore, in this experiment, we determined the time-dependent effects of LPS on heart rate (HR) and circadian gene expression in the mouse heart and liver. HR of the LPS group was significantly elevated 2 and 8 h after injection compared to the control group. A significant percent increase in HR was observed at ZT6, 12, and 18. LPS increased Tnfalpha mRNA expression in the heart and liver at ZT6, 18, and 24. A time-dependent effect of LPS on reduction of Per1 and Per2 gene expression was also observed in the heart and liver. In order to examine the effect of LPS on cell damage, we examined apoptosis-related gene expression after LPS injection. Bax mRNA expression level of the LPS group was higher than that of the control group 8 and 26 h after injection. On the other hand, Bcl2 mRNA expression level of the LPS group was lower than that of the control group 2 and 26 h after injection. Dexamethasone strongly attenuated the LPS-induced increase of serum TNFalpha without significant change in Per1 and Per2 gene expression in the heart. In conclusion, the present results demonstrated that LPS exerts a time-dependent inhibitory effect on Per1 and Per2 gene expression in the heart and liver. The chronopharmacological lethal effect of LPS may be related to the time-dependent increase of serum TNFalpha level and simultaneously high level of Per2 gene expression in the heart and liver between ZT12-18. Taken together, chronopharmacological effect of LPS may be related to not only sickness behavior syndrome and mortality, but also circadian rhythm systems.
Yamamura
Yusuke
Y
Department of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University, Wakamatsu-cho 2-2, Shinjuku-ku, Tokyo, 162-8480, Japan.
Yano
Ichiro
I
Kudo
Takashi
T
Shibata
Shigenobu
S
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001683:Biological Clocks / Q000187:drug effects / Q000235:genetics; D002940:Circadian Rhythm / Q000187:drug effects / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D056950:Period Circadian Proteins / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D005938:Glucocorticoids; D008070:Lipopolysaccharides; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase