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Cardiovascular Research Advance Access [Accepted Manuscript] published online on November 3, 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 remodeling

Takashi Kohno, MD1, Toshihisa Anzai, MD1, Kotaro Naito, MD1, Taku Miyasho, PhD2, Minoru Okamoto, PhD2, Hiroshi Yokota, PhD2, Shingo Yamada, PhD3, Yuichiro Maekawa, MD1, Toshiyuki Takahashi, MD1, Tsutomu Yoshikawa, MD1, Akitoshi Ishizaka, MD1 and Satoshi Ogawa, MD1

1 Cardiopulmonary Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan
2 Department of Veterinary Medicine, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan
3 Central Institute, Shino-test Corporation, Sagamihara, Japan

Correspondence: Toshihisa Anzai, MD, Cardiopulmonary Division, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan, Tel: +81-3-5363-3793, Fax: +81-3-3353-2502, E-mail: 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) remodeling 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/antiH) or control antibody (MI/C) to MI rats subcutaneously for 7 days. The mRNA levels of tumor necrosis factor-{alpha} and interleukin-1β and the number of macrophages in the infarcted area were reduced on day 3 in MI/antiH 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 remodeling, 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.

Time for primary review: 34 Days


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