1798-LB: STK25 Promotes Diabetic Atherosclerotic Plaque Formation via Septin2 Regulating Mitophagy

Introduction & Objective: Serine/Threonine protein kinase 25 (STK25) was reported to regulate lipid accumulation and activation of inflammatory and fibrotic pathways as well as oxidative and endoplasmic reticulum stress in human aortic endothelial cell. However, the direct substrate of STK25 in endothelial cells is not clear, and the mechanism of STK25 and its substrate in the diabetic atherosclerosis remained unknown. This study aimed to explore the substrate and potential mechanism of STK25 in the formation of diabetic atherosclerotic plaque.

Method: Male C57BL/6J mice were intraperitoneal injection of streptozotocin and tail-vein injection of the rAAV8-PCSK9 virus (5 ×10¹⁰ genome copies) or negative control to establish an diabetic atherosclerosis model. Thereafter, mice were fed a western-type diet. Morphological observation, blood triglyceride and cholesterol analysis, oil red O staining, immunofluorescent staining, electron microscope, real-time PCR, co-immunoprecipitation, and Western Blot were performed. Human aortic endothelial cells subjected to different concentrations of low density lipoprotein (LDL) was applied for assessing the related mechanism.

Result: STK25 increased, the endothelial barrier function was impaired, and mitophagy of aortic endothelial cells decreased in vivo and in vitro. While the silencing of STK25 reduces lipid accumulation and improve the mitophagy in aortic endothelial cells. And LC/MS and Co-IP showed that Septin2 had interaction with STK25. Moreover, STK25 regulates mitophagy of endothelial cell through phosphorylation of Septin2.

Conclusion: Together, we provide several lines of evidence that STK25 promoted diabetic atherosclerotic plaque formation, which is accounted for at least partly via septin2 regulating mitophagy.