Abstract 2588: Controlled Inflammation Induced by Injection of High Mobility Group Box 1 Recovers Post-Infarction Chronic Failing Heart
Background: The inflammatory response is an integral component of tissue repair and regeneration. High Mobility Group Box 1 (HMGB1) protein, originally identified as an abundant chromatin protein, has recently been shown to act as a strong pro-inflammatory mediator. In addition, it is suggetsed that HMGB1 secreted from necrotic grafted cells may play an important role in cell therapy-induced myocardial recovery. In this study, we investigated whether induction of controlled local inflammation by intramyocardial injection of HMGB1 would favorably modulate post-infarction chronic failing hearts.
Methods and Results: Three weeks after left coronary artery ligation in rat, 25μg of recombinant HMGB1 or control vehicle was intramyocardially injected into the border areas surrounding the infarct. At 28 days after injection, echocardiography showed that HMGB1 significantly improved the left ventricular ejection fraction (6.7±1.8% increase from pre-injection, n=10) compared to the control group (2.6±1.6% decrease, n=7, p<0.01). Immunolabelling showed that HMGB1-injection enhanced the recruitment of CD45+ inflammatory cells into the border areas at 3 days (88.9±8.9/mm2 in HMGB1 vs 45.6±5.1/mm2 in control, p<0.001). In contrast, accumulation of CD45+ cells into the infarct or the remote areas was not different between groups. Microarray analysis revealed that the expression profile of relevant inflammatory cytokines and chemokines were modulated by HMGB1-injection. At 28 days, reduced fibrosis (collagen volume fraction: 11.9±0.4% vs 15.2±0.6%, p<0.001) and enhanced neovascular formation (capillary density: 53.4±2.9/mm2 vs 35.4±2.1/mm2, p<0.001) were observed in the border areas in the HMGB1 group compared to the control.
Conclusion: Intramyocardial injection of HMGB1 was able to induce local controlled inflammation. Importantly, this was associated with a regenerative response to modulate adverse remodelling processes of the chronic failing myocardium which resulted in the improvement of cardiac function. These data suggest a role of HMGB1 in myocardial repair and its clinical utility for treating heart failure.