Metformin and caffeic acid phenethyl ester counteract hyperglycemia-induced endothelial dysfunction through growth differentiation factor 15 and heme oxygenase-1-associated signaling.

Hyperglycemia disrupts the redox homeostasis of endothelial cells and impairs their angiogenic capacity. In our in vitro study, we examined the regulation of growth differentiation factor 15 (GDF15) and heme oxygenase-1 (HO-1) in cultured human umbilical vein endothelial cells (HUVECs) and human aortic endothelial cells (HAECs) under high glucose conditions. Our findings revealed that exposure to elevated glucose levels (30 mM) reduced GDF15 and HO-1 expression, increased reactive oxygen species (ROS) levels, and decreased endothelial proliferation and angiogenesis in vitro; importantly, mannitol did not replicate these effects. Notably, metformin effectively restored GDF15 expression and secretion, reversed glucose-induced changes in AKT and AMPKα1/2 phosphorylation, enhanced HO-1 expression, reduced ROS accumulation, and improved in vitro angiogenic capacity. Similarly, caffeic acid phenethyl ester (CAPE) elevated GDF15 and HO-1 levels, decreased ROS, and reinstated angiogenesis under glucose stress in vitro. Knockdown experiments indicated a co-expression and functional interaction between GDF15 and HO-1, although the directionality of the pathway remains to be established. These cell-based findings highlight the potential of GDF15-HO-1-associated signaling as a glucose-responsive mechanism of endothelial stress and warrant further in vivo validation.