Scoping review of preclinical and clinical studies on the role of HMGB1 in heart disease

Abstract High Mobility Group Box 1 (HMGB1) is a critical regulator of cardiac injury and repair. However, there is conflicting evidence regarding whether HMGB1 is beneficial or deleterious. We evaluated and synthesised available evidence regarding the molecular functions as well as the clinical and therapeutic utility of HMGB1 in heart disease. We found that overall, the effects depend on the redox state and subcellular location, although most studies failed to identify these parameters clearly. Nuclear upregulation or exogenous administration of fully reduced HMGB1 was beneficial. The partially oxidised form of HMGB1 (dsHMGB1) in the cytoplasm depleted intranuclear HMGB1, and extracellular dsHMGB1 was proinflammatory. Clinically, elevated circulating HMGB1 levels correlate with disease severity and may be a useful prognostic biomarker. Future research should specify the subcellular location and redox state of HMGB1. The development of methods to identify the different redox isoforms would help uncover the therapeutic potential of this multifaceted protein.