Modulated inflammation by injection of high-mobility group box 1 recovers post-infarction chronically failing heart

Background-Inflammation plays an important role in the progress of adverse ventricular remodeling after myocardial infarction. High-mobility group box 1 (HMGB1) is a nuclear protein, which has recently been uncovered to also act as a modifier of inflammation when released. We hypothesized that HMGB1 injection could preferentially modulate local myocardial inflammation, attenuate ventricular remodeling, and subsequently improve cardiac performance of postinfarction chronic heart failure. Methods and Results-Three weeks after left coronary artery ligation, HMGB1 (2.5 mu g) or PBS was intramyocardially injected into rat hearts. At 28 days after injection, left ventricular ejection fraction was significantly improved after HMGB1 injection compared to PBS (39.3 +/- 1.4 versus 33.3 +/- 1.8%; P<0.01). Accumulation of CD45(+) inflammatory cells, two thirds of which were OX62(+) dendritic cells, in the peri-infarct area was significantly attenuated by HMGB1 injection. Dramatic changes in the expression of major proinflammatory cytokines were not detected by microarray or RT-PCR. Adverse ventricular remodeling including cardiomyocyte hypertrophy (cardiomyocyte cross-sectional area; 439 +/- 7 versus 458 +/- 6 mu m(2); P<0.05) and extracellular collagen deposition (collagen volume fraction; 11.9 +/- 0.4 versus 15.2 +/- 0.6%; P<0.01) was attenuated by HMGB1 injection. Analyses of signal transduction pathways revealed that HMGB1 injection activated ERK1/2, but not p38, Akt, and Smad3. Cardiac regeneration and neovascularization were not observed. Conclusion-HMGB1 injection modulated the local inflammation in the postinfarction chronically failing myocardium, particularly via reducing the accumulation of dendritic cells. This modulated inflammation resulted in attenuated fibrosis and cardiomyocyte hypertrophy, which thereby improved global cardiac function. These data suggest that HMGB1 may be valuable for the chronic heart failure treatment.