Increase of PCSK9 expression in diabetes promotes VEGFR2 ubiquitination to inhibit endothelial function and skin wound healing

This study is led by professor Jingsong Ou(Division of Cardiac Surgery, Cardiovascular Diseases Institute, The First Affiliated Hospital, Sun Yat-sen University) and professor Zhi-Jun Ou (Division of Hypertension and Vascular Diseases, Department of Cardiology, Heart Center, The First Affiliated Hospital, Sun Yat-sen University). Diabetic foot ulcers are a serious complication with a potential risk of disability in diabetic patients, with a high incidence and no effective drug treatment. Diabetes-induced vascular endothelial dysfunction is an important cause of poor healing of diabetic foot ulcers. However, its exact pathogenesis is still not fully understood. Previous studies have found that preprotein convertase baculin/kexin type 9 (PCSK9) is involved in the regulation of low-density lipoprotein (LDL) levels and cholesterol metabolism, and the application of PCSK9 inhibitors can reduce plasma LDL levels and treat coronary heart disease. Recently, PCSK9 has also received increasing attention for its other functions independent of lipid levels. However, whether PCSK9 is involved in the regulation of endothelial function in diabetes mellitus and the occurrence of poor healing of diabetic foot ulcers has not yet been reported.

Using a series of composite experiments, including clinical specimens, two diabetic mouse models (STZ and db/db), viral-related experiments, and protein profiling, this study found that PCSK9 expression was significantly increased in endothelial cells in the vessels of lower limb ulcers in patients with diabetes mellitus and in high glucose-treated vascular endothelium, and that plasma PCSK9 levels were elevated in patients with diabetes mellitus. Further studies revealed that PCSK9 was involved in high glucose-induced vascular endothelial dysfunction. A series of functional experiments demonstrated that silencing PCSK9 significantly improved impaired vascular endothelial function. It is well known that accumulation of oxygen free radicals (ROS) is an important factor contributing to endothelial dysfunction in diabetes, and the present study found that intervention with PCSK9 significantly reduced ROS production and increased nitric oxide (NO) production, suggesting that PCSK9 is involved in the regulation of endothelial damage in diabetic vessels. Mass spectrometry analysis revealed that PCSK9 is involved in the regulation of VEGFR2 as an important angiogenesis-related molecule. PCSK9 can induce VEGFR2 ubiquitination and promote VEGFR2 degradation by facilitating the binding of the E3 ubiquitin ligase NEDD4 to VEGFR2, thereby inhibiting the activation and expression of AKT/eNOS and ERK1/2 downstream of it, and suppressing the function of vascular endothelium and angiogenesis. Further, two diabetic mouse models (STZ and db/db mice) combined with in vivo viral interference as well as inhibitors revealed that intervention of endothelial PCSK9 could effectively improve diabetic vascular endothelial function and accelerate diabetic wound healing.

Therefore, the present study elucidates a novel mechanism of PCSK9 involved in endothelial dysfunction and inhibition of angiogenesis occurring in diabetes mellitus and high glucose induction, and demonstrates that PCSK9 inhibitors can be used not only as effective lipid-lowering drugs, but also for the treatment of diabetic wounds with poor wound healing and promotion of diabetic foot ulcer healing. More importantly, the present study demonstrated that PCSK9 is a key molecule in regulating both glucose metabolism and lipid metabolism, and is a core node of glucose metabolism and lipid metabolism.

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Increase of PCSK9 expression in diabetes promotes VEGFR2 ubiquitination to inhibit endothelial function and skin wound healing

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