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

Author:

Ye Ning1,Miao Linlin1,Wang Fengzhi2,Wu Shaojun1,Wu Boquan1,Zhou Ying1,Wang Chang1,Sun Guozhe1

Affiliation:

1. Department of Cardiovascular Medicine, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China

2. Department of Neurology, People's Hospital of Liaoning Province, People's Hospital of China Medical University, Shenyang, Liaoning 110016, China

Abstract

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.

Funder

National Natural Science Foundation of China

Publisher

Bentham Science Publishers Ltd.

Subject

Drug Discovery,Pharmacology

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