PAI-1 Upregulates YAP1 Expression, Suppresses Retinal Microvascular Endothelial Cell Proliferation, and Promotes Apoptosis Under High Glucose Induction

Background: Diabetic retinopathy (DR), characterized by retinal microvascular dysfunction, is a common complication of diabetes. Plasminogen Activator Inhibitor 1 (PAI-1), a key regulator of fibrinolysis and inflammation, has been implicated in the pathogenesis of DR, its exact role and underlying mechanisms remain unclear. The objective of this study aimed to investigate the role of PAI-1 in regulating the function of retinal microvascular endothelial cells (RMECs) under high glucose (HG) conditions and to explore the involvement of Yes-associated protein 1 (YAP1) in this process.Methods: RMECs were cultured and subjected to HG, PAI-1 overexpression, PAI-1 inhibitor (TM5441), YAP1 inhibitor (K-975) treatment, or their combinations. Cell viability was assessed using the cell counting kit-8 (CCK-8) assay. However, YAP1 expression was determined using western blot. The apoptosis rate in the RMECs was evaluated using flow cytometry and caspase-3 activity assay. Additionally, the levels of inflammatory cytokines and vascular endothelial growth factor (VEGF) were deter-mined using enzyme-linked immunosorbent assay (ELISA).Results: It was observed that HG treatment and overexpression of PAI-1 significantly increased YAP1 expression in RMECs. Furthermore, HG and overexpressed PAI-1 significantly reduced cell viability, while promoting apoptosis, inflammatory response, and angiogenesis in RMECs. However, treatment with PAI-1 inhibitor or the YAP1 inhibitor reversed these effects, leading to significantly increased (p < 0.01) cell viability and decreased (p < 0.01) apoptosis, inflammatory response, and angiogenesis.Conclusions: In conclusion, our findings suggest that PAI-1 upregulates YAP1 expression in RMECs under HG conditions, thereby inhibiting cell proliferation, and promoting apoptosis, inflammatory response, and angiogenesis. The use of PAI-1 inhibitor or YAP1 inhibitor can reverse these effects, highlighting the potential therapeutic value of targeting PAI-1 and YAP1 in the treatment of DR. These findings provide new insights into the underlying molecular mechanisms involved in the pathogenesis of DR and might contribute to the development of novel therapeutic strategies for this disease.