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Cardiovascular Research 2007 76(1):132-140; doi:10.1016/j.cardiores.2007.05.024
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Copyright © 2007, European Society of Cardiology

Silencing of caspase-8 and caspase-3 by RNA interference prevents vascular endothelial cell injury in mice with endotoxic shock

Naoyuki Matsudaa, Yasuo Takanob, Shun-ichiro Kageyamaa, Noboru Hatakeyamac, Kiyoshi Shakunagac, Isao Kitajimad, Mitsuaki Yamazakic and Yuichi Hattoria,*

aDepartment of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
bDepartment of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
cDepartment of Anesthesiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
dDepartment of Clinical Laboratory Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan

*Corresponding author. Tel.: +81 76 434 7260; fax: +81 76 434 5021. yhattori{at}med.u-toyama.ac.jp

Objectives Septic shock and sequential multiple organ failure remain the cause of death in septic patients. Vascular endothelial cell apoptosis may play a role in the pathogenesis of the septic syndrome. Caspase-8 is presumed to be the apex of the death receptor-mediated apoptosis pathway, whereas caspase-3 belongs to the "effector" protease in the apoptosis cascade. Synthetic small interfering RNAs (siRNAs) specifically suppress gene expression by RNA interference. Therefore, we evaluated the therapeutic efficacy of caspase-8/caspase-3 siRNAs in a murine model of polymicrobial endotoxic shock.

Methods Polymicrobial endotoxic shock was induced by cecal ligation and puncture (CLP) in BALB/c mice. In vivo delivery of siRNAs was performed by using a transfection reagent (Lipofectamine 2000) at 10 h after CLP. As a negative control, animals received non-sense (scrambled) siRNA.

Results Marked increases in caspase-8 and caspase-3 protein expression in CLP aortic tissues were strongly suppressed by treatment with caspase-8/caspase-3 siRNAs. This siRNA treatment prevented DNA ladder formation and less phosphorylation of the pro-apoptotic protein Bad seen in CLP aortic tissues. Transferase-mediated dUTP nick end labeling (TUNEL) revealed that the appearance of apoptosis in aortic endothelium after CLP was eliminated by this siRNA treatment. Although all of the control animals subjected to CLP died within 2 days, administration of caspase-8/caspase-3 siRNAs indefinitely (>7 days) improved the survival of CLP mice.

Conclusions Gene silencing of caspase-8 and caspase-3 with siRNAs provided profound protection against polymicrobial endotoxic shock. The prevention of vascular endothelial cell apoptosis appears to be, at least in part, responsible for their beneficial effects in endotoxic shock.

KEYWORDS Akt; Apoptosis; Endothelium; Endothelial nitric oxide synthase; Phosphatidylinositol 3-kinase; Endotoxic shock; Small interfering RNA


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