| Cardiovascular Research

Forgot password?

Wechat
Email
Sign Up

Use Wechat scan code to follow the official account directly sign in

Sweep WeChat yards

Use Wechat scan code to follow the official account directly sign in

the Qr Code is useless
Refresh

Use Wechat scan code to follow the official account directly sign in

Waiting for the show Qr Code...
Forgot password?

Sign Up
Confirm

Agreement onAcademic agreement

Sign In

home > search >

Author:

Naoyuki Matsuda Yasuo Takano Shun-ichiro Kageyama Noboru Hatakeyama Kiyoshi Shakunaga Isao Kitajima Mitsuaki Yamazaki Yuichi Hattori

Journal:

Cardiovascular Research

Issue Date:

2007

Abstract(summary):

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.

Page: