Exogenous high-mobility group box 1 improves myocardial recovery after acute global ischemia/reperfusion injury.
BACKGROUND
High-mobility group box 1 (HMGB1) is a mediator of inflammation with dose-dependent effects. In the setting of regional myocardial infarction, a high-dose HMGB1 treatment decreases myocardial function, whereas low-dose HMGB1 improves function; however, it is unknown what role HMGB1 has in the setting of global ischemia/reperfusion (I/R) injury. We hypothesized that a low-dose HMGB1 treatment would improve myocardial functional recovery and decrease infarct size after global I/R injury in association with increased levels of cardioprotective paracrine factors and decreased inflammation.


METHODS
Adult rat hearts were isolated and perfused using the Langendorff method and were subjected to global I/R and treatment with either the vehicle, 200-ng HMGB1, or 1-μg HMGB1. The treatment was administered during 1 min at the start of reperfusion, and myocardial function was measured for 60 min of reperfusion. At the end of reperfusion, the hearts were sectioned and incubated in triphenyltetrazolium chloride to assess myocardial infarct size or homogenized to measure levels of inflammatory cytokines and growth factors.


RESULTS
Postischemic treatment with 200-ng HMGB1 significantly improved myocardial functional recovery after global I/R in association with decreased infarct size and decreased interleukin-1 (IL-1), IL-6, IL-10, and vascular endothelial growth factor (VEGF) levels. In addition, 1-μg HMGB1 decreased myocardial inflammation but did not result in subsequent improvement in functional recovery.


CONCLUSIONS
In the setting of global I/R, 200-ng postischemic HMGB1 treatment improves myocardial function and decreases infarct size in association with suppressed myocardial inflammation. These results suggest a potential role for exogenous HMGB1therapy in the acute postischemic period.
Abarbanell
Aaron M
AM
Department of Surgery, Indiana University, 2017 Van Nuys Medical Science Building, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
Hartley
Jacob A
JA
Herrmann
Jeremy L
JL
Weil
Brent R
BR
Wang
Yue
Y
Manukyan
Mariuxi C
MC
Poynter
Jeffrey A
JA
Meldrum
Daniel R
DR
D000208:Acute Disease; D000818:Animals; D024243:HMGB1 Protein / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000032:analysis; D016753:Interleukin-10 / Q000096:biosynthesis; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D024243:HMGB1 Protein; D007375:Interleukin-1; D042461:Vascular Endothelial Growth Factor A; D016753:Interleukin-10