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Open Access Highly Accessed Research article

Targeted suppression of heme oxygenase-1 by small interference RNAs inhibits the production of bilirubin in neonatal rat with hyperbilirubinemia

Jinyong Wu12, Wen Su1, Youxin Jin3, Yi Shi3, Chune Li1, Wenwei Zhong1, Xuehong Zhang2, Zili Zhang4 and Zhenwei Xia1*

Author Affiliations

1 Ruijin Hospital Affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China

2 School of Life Science and Technology, Shanghai Jiao Tong University, Shanghai, PR China

3 State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, PR China

4 Department of Pediatrics, Oregon Health and Sciences University, Portland, Oregon, USA

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BMC Molecular Biology 2009, 10:77  doi:10.1186/1471-2199-10-77

Published: 1 August 2009

Abstract

Background

Excessive accumulation of bilirubin contributes to neonatal hyperbilirubinemia in rats. Heme oxygenase (HO) is one of the rate-limiting enzymes in catabolizing heme to bilirubin. In the present study, we investigated whether suppression of rat HO-1 (rHO-1) expression by small interference RNAs (siRNAs) reduces bilirubin levels in hyperbilirubinemic rats.

Results

Four pairs of siRNA targeting rHO-1 mRNA were introduced into BRL cells and compared for their inhibitory effect on the expression of rHO-1 gene and production of rHO-1 protein. The siRNA exhibiting the most potent effect on HO-1 expression and activity was then administered intraperitoneally to 7 to 9-day-old rats with hyperbilirubinemia. The siRNA distributed mostly in the liver and spleen of neonatal rat. Serum bilirubin levels and hepatic HO-1 expression were further evaluated. Systemic treatment of siRNA targeting rHO-1 reduced hepatic HO-1 expression and decreased the serum bilirubin levels in a time- and dose-dependent manner, and siRNA decreased the indirect bilirubin levels more effectively than Sn-protoporphyrin (SnPP), an HO-1 inhibitor.

Conclusion

siRNA targeting rHO-l attenuates hepatic HO-1 expression and serum bilirubin levels. Thus this study provides a novel therapeutic rationale for the prevention and treatment of neonatal hyperbilirubinemia.