High mobility group box 1: DAMPening the danger molecule in cardiovascular disease with exercise.

High mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP). During cellular stress, it leaves the nucleus and moves into the extracellular space, where it modulates the development of cardiovascular diseases (CVDs), a leading global cause of age-related mortality. While evidence indicates that HMGB1 is associated with both the progression and severity of CVDs, it also has a paradoxically beneficial role in mitigating tissue repair. Exercise training improves cardiovascular function and modulates systemic concentrations of HMGB1. Acute exercise induces the release of HMGB1 into systemic concentration, whereas long-term exercise training appears to reduce its systemic levels. This paradoxical response of HMGB1 to either short-term or chronic exercise, alongside its complex role in the pathogenesis of age-associated CVDs, makes it an intriguing subject for research. A potential explanation for this paradox may lie in HMGB1's capacity in regulating stem cell recruitment and tissue regeneration. This review explores the intricate interactions between HMGB1, exercise and CVDs, and discusses its potential both as a therapeutic target and a novel biomarker for tracking inflammatory signaling during exercise.