Key result
PAI-1 inhibition reduces hyperglycemia-induced vascular calcification, highlighting its role in diabetic VC development.
Why the study?
Vascular calcification is common in diabetes and linked to impaired fibrinolysis, but how fibrinolytic dysregulation contributes to vascular calcification remains unclear.
Does plasmin-PAI-1 imbalance contribute to hyperglycemia-induced vascular calcification?
Does plasmin-PAI-1 imbalance contribute to hyperglycemia-induced vascular calcification?
PAI-1 contributes to hyperglycemia-related vascular calcification, while plasmin exerts protective effects, suggesting a potential therapeutic target for diabetic vascular complications.
Should not yet change practice for diabetic VC; extends evidence for PAI-1's role and leaves open clinical translation.
Background: Vascular calcification (VC) is a frequent complication in diabetes and is linked to an increased risk of thrombotic cardiovascular events. Diabetes is characterized by impaired fibrinolysis, and accumulating evidence implicates fibrin deposition in VC progression. However, how fibrinolytic dysregulation contributes to VC remains unclear. Methods: We examined the role of fibrinolytic factors in VC using an established in vitro model. Vascular smooth muscle cells (VSMCs) were cultured under high-glucose conditions to evaluate glucose-induced VC and plasminogen activator inhibitor-1 (PAI-1) expression. In addition, exogenous plasmin stimulation was performed to assess its effects on VC progression and anti-calcific signaling. Results: High glucose enhanced VC and markedly increased PAI-1 expression. Inhibition of PAI-1 signaling attenuated glucose-induced VC, indicating its involvement in VC development under hyperglycemia. Conversely, exogenous plasmin reduced VC under normoglycemic conditions. Short-term plasmin stimulation activated AMP-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS), both known inhibitors of VC. Conclusion: These findings suggest that PAI-1 contributes to hyperglycemia-related VC, whereas plasmin exerts protective effects partly through AMPK–eNOS activation. Modulating plasmin activity or targeting PAI-1 may represent potential therapeutic approaches to prevent VC progression in diabetes.
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Kanno et al. (2026) studied this question. Inhibition of PAI-1 signaling significantly reduced hyperglycemia-induced vascular calcification, highlighting its role in VC development in diabetes.
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