Cathepsin D Attenuates the Proliferation of Vascular Smooth Muscle Cells Induced by the AGE/RAGE Pathway by Suppressing the ERK Signal

MAPK/ERK通路 血管平滑肌 组织蛋白酶D 基因敲除 小发夹RNA 细胞生长 免疫沉淀 细胞生物学 化学 癌症研究 信号转导 分子生物学 生物 内分泌学 生物化学 细胞凋亡 基因 平滑肌
作者
Ning Ye,Linlin Miao,Fengzhi Wang,Shaojun Wu,Boquan Wu,Ying Zhou,Chang Wang,Guozhe Sun
出处
期刊:Current Pharmaceutical Design [Bentham Science Publishers]
卷期号:29 (30): 2387-2395 被引量:2
标识
DOI:10.2174/0113816128261894231012144719
摘要

Background: In this study, we aimed to clarify the role and mechanism by which Cathepsin D (CTSD) mediates the advanced glycation end products (AGEs)-induced proliferation of vascular smooth muscle cells (VSMCs). Methods: We conducted a Western blotting assay and co-immunoprecipitation assay to detect the expression of target proteins and the interaction between different proteins. Cell Counting Kit-8 (CCK-8) assay and 5- ethynyl-2’-deoxyuridine (EdU) were used to evaluate the proliferation. Results: AGEs significantly promoted phenotypic switching and proliferation of VSMCs in a concentration-dependent manner. This effect of AGEs was accompanied by inhibition of CTSD. Both the proliferation of VSMCs and inhibition of CTSD induced by AGEs could be attenuated by the specific inhibitor of the receptor for advanced glycation end products (RAGE), FPS-ZM1. Overexpression of CTSD significantly alleviated these effects of AGEs on VSMCs. The mechanism of CTSD action in VSMCs was also explored. Overexpression of CTSD reduced the activation of p-ERK caused by AGEs. By contrast, the knockdown of CTSD, elicited using a plasmid containing short hairpin RNA (shRNA) against CTSD, further increased the activation of p-ERK compared to AGEs alone. Additionally, co-immunoprecipitation studies revealed an endogenous interaction between CTSD, a protease, and p-ERK, its potential substrate. Conclusion: It has been demonstrated that CTSD downregulates the level of phosphorylated ERK by degrading its target, and this interaction plays a critical role in the proliferation of VSMCs induced by the AGE/RAGE axis. These results provide a novel insight into the prevention and treatment of vascular complications in diabetes.
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