12‐HETE/GPR31 induces endothelial dysfunction in diabetic retinopathy

• Published in: The FASEB journal 2024-09, Vol.38 (18), p.e70064-n/a
• Main Authors: Chen, Shuli, Qin, Xinran, Sun, Yu, Ma, Zhenlin, Niu, Chen, Xu, Yi, Lu, Lina, Zou, Haidong
• Format: Article
• Language: English
• Subjects: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid - metabolism; Animals; arachidonic acid; Cells, Cultured; diabetes; Diabetes Mellitus, Experimental - metabolism; Diabetic Retinopathy - etiology; Diabetic Retinopathy - metabolism; Diabetic Retinopathy - pathology; eicosanoids; Endothelial Cells - metabolism; epidemiology; Female; high‐fat diet; Humans; inflammation; lipoxygenase; Male; Mice; Mice, Inbred C57BL; Middle Aged; p38 MAPK pathway; Prospective Studies; Receptors, G-Protein-Coupled - metabolism; retina; retinal microvascular endothelial cell
• ISSN: 0892-6638; 1530-6860; 1530-6860
• DOI: 10.1096/fj.202401362R

12‐hydroxyeicosatetraenoic acid (12‐HETE), a major metabolite of arachidonic acid, is converted by 12/15‐lipoxygenase and implicated in diabetic retinopathy (DR). Our previous study demonstrated a positive correlation between 12‐HETE and the prevalence of DR. However, reasons for the increased production of 12‐HETE are unclear, and the underlying mechanisms through which 12‐HETE promotes DR are unknown. This study aimed to elucidate the correlation between 12‐HETE and DR onset, investigate potential mechanisms through which 12‐HETE promotes DR, and seek explanations for the increased production of 12‐HETE in diabetes. We conducted a prospective cohort study, which revealed that higher serum 12‐HETE levels could induce DR. Additionally, G protein‐coupled receptor 31 (GPR31), a high‐affinity receptor for 12‐HETE, was expressed in human retinal microvascular endothelial cells (HRMECs). 12‐HETE/GPR31‐mediated HRMEC inflammation occurred via the p38 MAPK pathway. 12‐HETE levels were significantly higher in the retina of mice with high‐fat diet (HFD)‐ and streptozotocin (STZ)‐induced diabetes than in those with only STZ‐induced diabetes and healthy controls. They were positively correlated with the levels of inflammatory cytokines in the retina, indicating that HFD could induce increased 12‐HETE synthesis in patients with diabetes in addition to hyperglycemia. Conclusively, 12‐HETE is a potential risk factor for DR. The 12‐HETE/GPR31 axis plays a crucial role in HRMEC dysfunction and could be a novel target for DR prevention and control. Nevertheless, further research is warranted to provide comprehensive insights into the complex underlying mechanisms of 12‐HETE in DR. Higher serum 12‐HETE levels could induce diabetic retinopathy (DR) in patients with diabetes. G protein‐coupled receptor 31 (GPR31) was a high‐affinity receptor for 12‐HETE. 12‐HETE/GPR31 could induce retinal endothelial inflammation via the p38 MAPK pathway. 12‐HETE levels were significantly higher in the retina of mice with high‐fat diet (HFD)‐ and streptozotocin (STZ)‐induced diabetes than in those with only STZ‐induced diabetes and healthy controls, indicating that HFD could induce increased 12‐HETE synthesis in patients with diabetes.