The emerging role of heparanase in cardiovascular diseases: Pathophysiology, clinical outcomes, and therapeutic perspectives

Endothelial dysfunction, inflammation, atherosclerosis, thrombosis, and extracellular matrix remodeling represent the key pathophysiological processes underlying cardiovascular diseases. Heparanase, the sole mammalian endo-β-D-glucuronidase that cleaves heparan sulfate chains, serves as a key mediator linking these interrelated processes. Through glycocalyx disruption, it enhances vascular permeability, facilitates inflammatory cell recruitment, and promotes tissue factor–driven thrombosis, thereby promoting vascular inflammation and a prothrombotic state. The enzyme contributes to multiple cardiovascular pathologies, including atherosclerosis, thrombosis, restenosis, calcific valvular heart disease, diabetic cardiomyopathy, pulmonary vascular remodeling, and ischemia–reperfusion injury. Notably, its effects are context-dependent, reflecting a “dual role”: excessive activity enhances vascular injury and plaque instability, whereas basal expression may support cardiomyocyte survival and adaptive remodeling under stress conditions. This review discusses molecular mechanisms and therapeutic implications, integrating data from experimental and clinical studies to provide a unified understanding of heparanase biology in the cardiovascular system. Emphasis is placed on translational prospects, highlighting heparanase modulation as both a diagnostic biomarker and a potential therapeutic target for preventing or attenuating cardiovascular disease progression. Heparanase acts as a central mediator linking endothelial dysfunction, inflammation, thrombosis, and extracellular matrix remodeling in cardiovascular pathology. By degrading heparan sulfate chains within the vascular glycocalyx and matrix, it increases permeability, promotes inflammatory cell recruitment, and enhances tissue factor–driven coagulation. These mechanisms contribute to the progression of atherosclerosis, thrombosis and restenosis, valvular calcification, diabetic cardiomyopathy, and myocardial injury. The enzyme thus represents a unifying molecular link among diverse cardiovascular disorders, serving both as a pathogenic effector and a potential biomarker and therapeutic target.