Small Interfering RNA Targeting Heme Oxygenase-1 (HO-1) Reinforces Liver Apoptosis Induced by Ischemia-Reperfusion Injury in Mice: HO-1 Is Necessary for Cytoprotection

被引：43

作者：

Ke, Bibo ^{[1
]}

Shen, Xiu-Da ^{[1
]}

Gao, Feng ^{[1
]}

Qiao, Bo ^{[1
]}

Ji, Haofeng ^{[1
]}

Busuttil, Ronald W. ^{[1
]}

Volk, Hans-Dieter ^{[2
]}

Kupiec-Weglinski, Jerzy W. ^{[1
]}

机构：

[1] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Dumont UCLA Transplant Ctr, Los Angeles, CA 90095 USA

[2] Humboldt Univ, Inst Med Immunol, D-10117 Berlin, Germany

来源：

HUMAN GENE THERAPY | 2009年 / 20卷 / 10期

关键词：

COLD ISCHEMIA/REPERFUSION INJURY; ZUCKER RAT LIVERS; CARBON-MONOXIDE; GENE-TRANSFER; NEUTROPHIL INFILTRATION; MEDIATED APOPTOSIS; ENDOTHELIAL-CELLS; EXPRESSION; NECROSIS; PATHWAY;

D O I：

10.1089/hum.2009.049

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 [微生物学]; 090105 [作物生产系统与生态工程];

摘要：

We have shown that overexpression of heme oxygenase-1 (HO-1) prevents the liver inflammation response leading to ischemia and reperfusion injury (IRI). This study was designed to explore the precise function and mechanism of HO-1 cytoprotection in liver IRI by employing a small interfering RNA ( siRNA) that effectively suppresses HO-1 expression both in vitro and in vivo. Using a partial lobar liver warm ischemia model, mice were injected with HO-1 siRNA/nonspecific control siRNA or Ad-HO-1/Ad-beta-gal. Those treated with HO-1 siRNA showed increased serum glutamic-oxaloacetic transaminase levels, significant liver edema, sinusoidal congestion/cytoplasmic vacuolization, and severe hepatocellular necrosis. In contrast, Ad-HO-1-pretreated animals revealed only minimal sinusoidal congestion without edema/vacuolization or necrosis. Administration of HO-1 siRNA significantly increased local neutrophil accumulation and the frequency of apoptotic cells. Mice treated with HO-1 siRNA were characterized by increased caspase-3 activity and reduced HO-1 expression, whereas those given Ad-HO-1 showed decreased caspase-3 activity and increased HO-1/Bcl-2/Bcl-xL, data confirmed by use of an in vitro cell culture system. Thus, by using an siRNA approach this study confirms that HO-1 provides potent cytoprotection against hepatic IRI and regulates liver apoptosis. Indeed, siRNA provides a powerful tool with which to study gene function in a wide range of liver diseases.

引用

页码：1133 / 1142

页数：10

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