Skip Navigation


Cardiovascular Research Advance Access first published online on October 16, 2009
This version [Corrected Proof] published online on November 21, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp342
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplementary Data
Right arrow All Versions of this Article:
cvp342v2    most recent
cvp342v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Kobayashi, T.
Right arrow Articles by Kugiyama, K.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kobayashi, T.
Right arrow Articles by Kugiyama, K.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Mice lacking the glutamate-cysteine ligase modifier subunit are susceptible to myocardial ischaemia–reperfusion injury

Tsuyoshi Kobayashi1, Yosuke Watanabe1, Yukio Saito1, Daisuke Fujioka1, Takamitsu Nakamura1, Jun-ei Obata1, Yoshinobu Kitta1, Toshiaki Yano1, Kenichi Kawabata1, Kazuhiro Watanabe1, Hideto Mishina1, Sadahiro Ito2 and Kiyotaka Kugiyama1,*

1 Department of Internal Medicine II, University of Yamanashi, Faculty of Medicine, 1110 Shimokato, Chuo, Yamanashi409-3898, Japan
2 Center for Life Science Research, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan

* Corresponding author. Tel: +81 55 273 9590, Fax: +81 55 273 6749, Email: kugiyama{at}yamanashi.ac.jp

Aims: Glutamate-cysteine ligase (GCL), a rate-limiting enzyme for glutathione (GSH) synthesis, is composed of catalytic and modifier subunits. This study examined the pathogenic role of GCL modifier subunits (GCLM) in myocardial ischaemia–reperfusion (I/R) injury using mice lacking the GCLM (GCLM–/–).

Methods and results: The GCLM–/–mice had an increase in myocardial I/R injury and apoptosis in ischaemic myocardium compared with GCLM+/+ mice. There was a decrease in mitochondrial glutathione (GSH) levels in ischaemic myocardium that was more pronounced in GCLM–/– mice than in GCLM+/+ mice (12 vs. 55% of baseline GCLM+/+, respectively). The ESR signal intensity of the dimethyl-1-pyrroline-N-oxide-hydroxyl radical adducts in ischaemic myocardium was higher in GCLM–/– mice than in GCLM+/+ mice. Hypoxia–reoxygenation induced greater mitochondrial damage in cultured cardiomyocytes from GCLM–/– mice than from GCLM+/+ mice, as evidenced by a reduced membrane potential and increased protein carbonyl content in isolated mitochondria, together with enhanced cytochrome c translocation into the cytosol. Administration of GSH ethyl-ester attenuated myocardial I/R injury and reversed the mitochondrial damage in parallel with the mitochondrial GSH restoration in the myocardium or the cardiomyocytes of GCLM–/– mice.

Conclusion: GCLM–/– mice were susceptible to myocardial I/R injury partly through an increased vulnerability of mitochondria to oxidative damage owing to mitochondrial GSH reduction.

KEYWORDS Antioxidant; Glutathione; Ischaemia–reperfusion injury; Mitochondria

Time for primary review: 19 days


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.