The Role of HMGB1 in Cardiovascular Biology: Danger Signals

Significance: Cardiovascular disease (CVD) is the leading cause of mortality worldwide. Accumulating evidence shows that dysregulated immune response contributes to several types of CVDs such as atherosclerosis and pulmonary hypertension (PH). Vascular intimal impairment and low-density lipoprotein oxidation trigger a complex network of innate immune responses and sterile inflammation. Recent Advances: High-mobility group box 1 (HMGB1), a nuclear DNA-binding protein, was recently discovered to function as a damage-associated molecular pattern molecule (DAMP) that initiates the innate immune responses. These findings lead to the understanding that HMGB1 plays a critical role in the inflammatory response in the pathogenesis of CVD. Critical Issues: In this review, we highlight the role of extracellular HMGB1 as a proinflammatory mediator as well as a DAMP in coronary artery disease, cerebral artery disease, peripheral artery disease, and PH. Future Directions: A key focus for future researches on HMGB1 location, structure, modification, and signaling will reveal HMGB1's multiple functions and discover a targeted therapy that can eliminate HMGB1-mediated inflammation without interfering with adaptive immune responses. Antioxid. Redox Signal. 23, 1351-1369.