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Cardiovascular Research Advance Access first published online on September 30, 2009
This version [Corrected Proof] published online on October 22, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp323
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Induction of MAPK phosphatase-1 by hypothermia inhibits TNF-{alpha}-induced endothelial barrier dysfunction and apoptosis

Dan Yang1, Ping Xie1, Shubin Guo2,* and Huihua Li1,*

1 Department of Pathology and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, #5 Dong Dan San Tiao, Beijing 100005, China
2 Department of Emergency Medicine, Peking Union Medical Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, #1 Shuai Fu Hu Tong, Beijing 100730, China

* Corresponding author. Tel: +86 10 6529 6494 (H.L.)/+86 10 6529 5303 (S.G.), Fax: +86 10 6529 6494 (H.L.)/+86 10 6529 5303 (S.G.), Email: hhli1935{at}yahoo.cn (H.L.)/shubinguo{at}medmail.com.cn (S.G.)

Aims: Hypothermia therapy has been shown to confer robust protection against brain injury and cardiac arrest. However, the mechanisms underlying endothelial cell protection of hypothermia have not yet been completely elucidated. Here, we investigated molecular effects of hypothermia on tumour necrosis factor-{alpha} (TNF-{alpha})-induced endothelial barrier dysfunction and apoptosis.

Methods and results: Human umbilical vein endothelial cells (HUVECs) treated with TNF-{alpha} were incubated under normothermia (37°C) or hypothermia (3°C). Endothelial permeability, actin alterations, and apoptosis were examined. The protein levels were determined by immunoblot analysis. Treatment of HUVECs with TNF-{alpha} resulted in a significant increase of permeability, actin reorganization, and apoptosis. Hypothermia markedly attenuated TNF-{alpha}-induced effects. The inhibitory action of hypothermia on stress fibre formation was mediated via inactivation of p38 mitogen-activated protein kinase (MAPK)/heat shock protein 27 (HSP27), and the decrease in TNF-{alpha}-induced apoptosis by hypothermia was associated with inhibition of p38 MAPK and c-Jun N-terminal kinase (JNK) activity. Hypothermia had no action on p38 MAPK and JNK upstream kinases MAPK kinase 3/6 (MKK3/6) and MAPK kinase 7 (MKK7), but it markedly induced the expression of MAPK phosphatase-1 (MKP-1). Furthermore, siRNA experiments showed that MKP-1 was an important mediator of hypothermia in reducing TNF-{alpha}-induced inflammatory responses and activation of p38 MAPK and JNK in HUVECs.

Conclusion: These results for the first time demonstrate that hypothermia protects against TNF-{alpha}-induced endothelial barrier dysfunction and apoptosis through an MKP-1-dependent mechanism.

KEYWORDS Hypothermia; MAPK phosphatase-1; TNF-{alpha}; Endothelial barrier dysfunction; Apoptosis

Time for primary review: 31 days


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