Wu Jinyong, Su Wen, Jin Youxin, Shi Yi, Li Chune, Zhong Wenwei, Zhang Xuehong, Zhang Zili, Xia Zhenwei
Ruijin Hospital Affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China.
BMC Mol Biol. 2009 Aug 1;10:77. doi: 10.1186/1471-2199-10-77.
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.
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.
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.
胆红素的过度积累会导致大鼠出现新生儿高胆红素血症。血红素加氧酶（HO）是血红素分解代谢为胆红素过程中的限速酶之一。在本研究中，我们调查了小干扰RNA（siRNA）抑制大鼠HO-1（rHO-1）表达是否能降低高胆红素血症大鼠的胆红素水平。
将四对靶向rHO-1 mRNA的siRNA导入BRL细胞，并比较它们对rHO-1基因表达和rHO-1蛋白产生的抑制作用。然后将对HO-1表达和活性表现出最有效作用的siRNA腹腔注射给7至9日龄的高胆红素血症大鼠。该siRNA主要分布在新生大鼠的肝脏和脾脏中。进一步评估血清胆红素水平和肝脏HO-1表达。全身性给予靶向rHO-1的siRNA可降低肝脏HO-1表达，并以时间和剂量依赖性方式降低血清胆红素水平，且siRNA降低间接胆红素水平的效果比HO-1抑制剂锡原卟啉（SnPP）更有效。
靶向rHO-1的siRNA可减弱肝脏HO-1表达和血清胆红素水平。因此，本研究为新生儿高胆红素血症的预防和治疗提供了一种新的治疗原理。
