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Cardiovascular Research Advance Access first published online on November 3, 2008
This version [Corrected Proof] published online on December 2, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn291
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Role of high-mobility group box 1 protein in post-infarction healing process and left ventricular remodelling

Takashi Kohno1, Toshihisa Anzai1,*, Kotaro Naito1, Taku Miyasho2, Minoru Okamoto2, Hiroshi Yokota2, Shingo Yamada3, Yuichiro Maekawa1, Toshiyuki Takahashi1, Tsutomu Yoshikawa1, Akitoshi Ishizaka1 and Satoshi Ogawa1

1 Cardiopulmonary Division, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
2 Department of Veterinary Medicine, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan
3 Central Institute, Shino-Test Corporation, Sagamihara, Japan

* Corresponding author. Tel: +81 3 5363 3793; fax: +81 3 3353 2502. E-mail address: anzai{at}cpnet.med.keio.ac.jp

Aims: High-mobility group box 1 protein (HMGB1) is one of the recently defined damage-associated molecular pattern molecules derived from necrotic cells and activated macrophages. We investigated clinical implications of serum HMGB1 elevation in patients with acute myocardial infarction (MI). Then, we evaluated the effect of HMGB1 blockade on post-MI left ventricular (LV) remodelling in a rat MI model.

Methods and results: Serum HMGB1 levels were examined in patients with ST-elevation MI (n = 35). A higher peak serum HMGB1 level was associated with pump failure, cardiac rupture, and in-hospital cardiac death. Then, an experimental MI model was induced in male Wistar rats. The mRNA and protein expression of HMGB1 were increased in the infarcted area compared with those values observed in sham-operated rats. We administered neutralizing anti-HMGB1 antibody (MI/anti-H) or control antibody (MI/C) to MI rats subcutaneously for 7 days. The mRNA levels of tumour necrosis factor-{alpha} and interleukin-1β and the number of macrophages in the infarcted area were reduced on day 3 in MI/anti-H rats compared with MI/C rats. Interestingly, HMGB1 blockade resulted in thinning and expansion of the infarct scar and marked hypertrophy of the non-infarcted area on day 14.

Conclusion: Elevated serum HMGB1 levels were associated with adverse clinical outcomes in patients with MI. However, HMGB1 blockade in a rat MI model aggravated LV remodelling, possibly through impairment of the infarct-healing process. HMGB1, a novel predictor of adverse clinical outcomes after MI, may have an essential role in the appropriate healing process after MI.

KEYWORDS Heart failure; Infarction; Cytokines; Remodelling; Infection/inflammation

Time for primary review: 34 days


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