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

Cardiopulmonary Division, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Cardiovascular Research (Impact Factor: 5.94). 12/2008; 81(3):565-73. DOI: 10.1093/cvr/cvn291
Source: PubMed


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.
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-1beta 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.
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.

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    • "In the infarcted myocardium of rodents the expression of HMGB1 is upregulated after 2 [82] or 3 days [95] depending on the model used. Furthermore, the elevated levels of HMGB1 in patients with acute coronary syndrome [95, 96] are associated with a decreased heart rate recovery, a marker of autonomic function defined as the fall in heart rate during the first minutes of exercise [97], and adverse LV remodeling [98] and predict secondary events, such as pump failure and cardiac rupture [95]. This might reflect that increased amounts of HMGB1 are detrimental. "
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    • "HMGB1 can be actively secreted by activated immune cells or passively released by necrotic cells, including cardiomyocytes [8, 9]. It has been reported that the serum HMGB1 level in patients with endotoxemia, sepsis, hemorrhagic shock, rheumatoid arthritis, type 2 diabetes, hypertension, and ST-elevation myocardial infarction is significantly increased, and high serum HMGB1 level has been associated with pump failure, cardiac rupture, and inhospital cardiac death [10–15]. Furthermore, plasma levels of HMGB1 have been correlated with the severity of injury and tissue hypoperfusion [16]. "
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