Abstract 1395: Role of High Mobility Group Box 1 Protein in Post-Infarction Healing Process and Left Ventricular Remodeling

Abstract

Background: The appropriate infarct healing process is prerequisite for preventing left ventricular (LV) remodeling after myocardial infarction (MI). High mobility group box1 protein (HMGB1) is derived from necrotic cells and activated macrophages and involved in tissue repair as immunostimulatory signal. However, the role of HMGB1 in post-MI LV remodeling is unknown. Methods and Results: We examined 35 patients with first ST-elevated acute MI. Peak serum HMGB1 level, determined by serial measurements (q. 6h), did not differ in age, sex, coronary risk factors and infarct site. Its peak level was markedly higher in patients with adverse in-hospital clinical outcomes, including pump failure, cardiac rupture, LV aneurysm and cardiac death, compared with those without (all p<0.05). Then we performed experimental study using rat MI model, induced by permanent left coronary ligation. Anti-HMGB1 antibodies (1 mg/day, MI/antiH, n=20) or control antibodies (MI/C, n=20) were injected subcutaneously every 24 hours for 7 days. Sham-operated rats served as controls (n=10). Quantitative RT-PCR and immunoblotting showed that HMGB1 expression was increased in the infarcted area peaking at day 3 in MI/C compared with sham (p<0.05). Its expression was localized in myocytes and inflammatory cells by immunohistochemistry. The mRNA level of TNF-α (−48%, p=0.03) and IL1-β (−44%, p=0.02) and the number of infiltrated macrophages (p=0.04) in the infarcted area were markedly reduced at day 3 in MI/antiH compared with MI/C. Echocardiographic and hemodynamic studies at day 7 showed increased LV end-diastolic dimension (p=0.03), LVEDP (p=0.03), and decreased LV max dP/dt (p=0.01) in MI/antiH compared with MI/C. Histologically, scar thinning in the infarcted area (0.53±0.23 vs 0.68±0.21 mm, p=0.02) and hypertrophy in the non-infarcted myocardium (2.01±0.23 vs 1.63±0.21 mm, p=0.03) were more prominent in MI/antiH compared with MI/C at day 14. Conclusions: Elevation of serum HMGB1 level is associated with adverse clinical outcomes in patients with acute MI. However, blockade of HMGB1 in rat MI model aggravated early LV remodeling through impaired infarct healing and advanced scar thinning, suggesting an essential role of HMGB1 in the appropriate repairing process after MI.