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


CONCLUSIONS
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.
Wu
Jinyong
J
Ruijin Hospital Affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China. chach84@sina.com
Su
Wen
W
Jin
Youxin
Y
Shi
Yi
Y
Li
Chune
C
Zhong
Wenwei
W
Zhang
Xuehong
X
Zhang
Zili
Z
Xia
Zhenwei
Z
D000818:Animals; D000831:Animals, Newborn; D001663:Bilirubin / Q000096:biosynthesis* / Q000097:blood; D002460:Cell Line; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics* / Q000378:metabolism; D006427:Hemin / Q000494:pharmacology; D006932:Hyperbilirubinemia / Q000201:enzymology* / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019076:Transgenes
D034741:RNA, Small Interfering; D006427:Hemin; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D001663:Bilirubin