Qin Peiliang, Zhou Peng, Huang Yating, Long Binbin, Gao Ruikang, Zhang Shan, Zhu Bingjie, Li Yi-Qing, Li Qin
Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
General Surgery Department, Taihe Hospital Affiliated to Hubei University of Medicine, Shiyan, Hubei, China.
Cell Death Discov. 2024 May 29;10(1):263. doi: 10.1038/s41420-024-02030-2.
Diabetic foot ulcer (DFU) is a prevalent complication of diabetes that poses significant challenges in terms of treatment and management. It is characterized by heightened endothelial apoptosis and impaired angiogenesis. In this study, we aimed to investigate the role of protein kinase Cδ (PKCδ) in regulating endothelial apoptosis in diabetic wounds by promoting cholesterol biosynthesis. The expression of PKCδ was increased in human umbilical vascular endothelial cells (HUVECs) cultivated in high glucose medium and skin tissue isolated from diabetic mice. High glucose-induced HUVECs apoptosis was reduced by PKCδ inhibition with siRNA or rottlerin. RNA-seq identified two enzymes, 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), as the downstream of PKCδ. PKCδ knockdown or inhibition suppressed the expression of HMGCS1 and HMGCR and lowered free cholesterol (FC) levels. Cholesterol restored high glucose-induced apoptosis in siRNA- or rottlerin-treated HUVECs. In vivo use of rosuvastatin calcium, an inhibitor of HMGCR, downregulated free cholesterol levels and accelerated the wound healing process. In conclusion, PKCδ expression in endothelial cells was activated by high glucose, which subsequently upregulates the expression of two enzymes catalyzing cholesterol biosynthesis, HMGCS1 and HMGCR. Enhanced cholesterol biosynthesis raises free cholesterol levels, promotes endothelial apoptosis, and finally delays wound healing.
糖尿病足溃疡（DFU）是糖尿病常见的并发症，在治疗和管理方面带来重大挑战。其特征是内皮细胞凋亡增加和血管生成受损。在本研究中，我们旨在探讨蛋白激酶Cδ（PKCδ）通过促进胆固醇生物合成在调节糖尿病伤口内皮细胞凋亡中的作用。在高糖培养基中培养的人脐静脉血管内皮细胞（HUVECs）和从糖尿病小鼠分离的皮肤组织中，PKCδ的表达增加。用siRNA或rottlerin抑制PKCδ可减少高糖诱导的HUVECs凋亡。RNA测序确定了两种酶，3-羟基-3-甲基戊二酰辅酶A合酶1（HMGCS1）和3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR），作为PKCδ的下游。PKCδ基因敲低或抑制可抑制HMGCS1和HMGCR的表达并降低游离胆固醇（FC）水平。胆固醇可恢复siRNA或rottlerin处理的HUVECs中高糖诱导的凋亡。体内使用HMGCR抑制剂瑞舒伐他汀钙可下调游离胆固醇水平并加速伤口愈合过程。总之，高糖激活内皮细胞中PKCδ的表达，随后上调催化胆固醇生物合成的两种酶HMGCS1和HMGCR的表达。增强的胆固醇生物合成提高游离胆固醇水平，促进内皮细胞凋亡，最终延迟伤口愈合。
