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Experimental Biology and Medicine 232:495-502 (2007)
© 2007 Society for Experimental Biology and Medicine

ORIGINAL RESEARCH ARTICLE

Reduction of Bilirubin by Targeting Human Heme Oxygenase-1 Through siRNA

Zhen-Wei Xia*,1,2, Chun-E Li*,2, You-Xin Jin{dagger}, Yi Shi{dagger}, Li-Qing Xu*, Wen-Wei Zhong*, Yun-Zhu Li*, Shan-Chang Yu* and Zi-Li Zhang{ddagger}

* Department of Pediatrics, Ruijin Hospital, Medical School, Shanghai Jiaotong University, 200025, Shanghai, China; {dagger} State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031, Shanghai, China; and {ddagger} Department of Pediatrics, Oregon Health and Sciences University, Portland, Oregon 97239

To whom requests for reprints should be addressed at 1 Department of Pediatrics, Ruijin Hospital, Ruijin 2nd Road 197, Shanghai 200025, China. E-mail: xzw63{at}hotmail.com

Neonatal hyperbilirubinemia is a common clinical condition caused mainly by the increased production and decreased excretion of bilirubin. Current treatment is aimed at reducing the serum levels of bilirubin. Heme oxygenase-1 (HO-1) is a rate-limiting enzyme that generates bilirubin. In this study we intended to suppress HO-1 using the RNA interference technique. Small interfering RNA (siRNA)-A, -B, and -C were designed based on human HO-1 (hHO-1) mRNA sequences. siRNA was transfected into a human hepatic cell line (HL-7702). hHO-1 transcription and protein levels were then determined. In addition, the inhibitory effect of siRNA on hHO-1 was assessed in cells treated with hemin or transfected with an hHO-1 plasmid. siRNA-C showed the most potent suppressive effect on hHO-1. This inhibition is dose and time dependent. Compared with control, both hemin and hHO-1 plasmids up-regulated hHO-1 expression in HL-7702 cells. However, the up-regulation was significantly attenuated by siRNA-C. Furthermore, the decrease in hHO-1 activity was coincident with the suppression of its transcription. Finally, siRNA-C was shown to reduce hHO-1 enzymatic activity and bilirubin levels. Thus, this study provides a novel therapeutic rationale by blocking bilirubin formation via siRNA for preventing and treating neonatal hyperbilirubinemia and bilirubin encephalopathy at an early clinical stage.

Key Words: heme oxygenase • RNA-mediated interference • small interfering RNA • bilirubin • hyperbilirubinemia






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