Endocytosis of Peptidase Inhibitor SerpinE2 promotes Myocardial Fibrosis through activating ERK1/2 and β-catenin Signaling Pathways

Cardiac fibrosis is one of the common pathological processes in many cardiovascular diseases characterized by excessive extracellular matrix deposition. SerpinE2 is a kind of protein that inhibits peptidase in extracellular matrix and up-regulated tremendously in mouse model of cardiac fibrosis indu...

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Bibliographic Details
Published in:International journal of biological sciences 2022, Vol.18 (16), p.6008-6019
Main Authors: Li, Chao, Lv, Li-Fang, Qi-Li, Mu-Ge, Yang, Rui, Wang, Yu-Jing, Chen, Shuang-Shuang, Zhang, Ming-Xiu, Li, Tian-Yu, Yu, Tong, Zhou, Yu-Hong, Liang, Hai-Hai, Shan, Hong-Li, Li, Xue-Lian
Format: Article
Language:English
Subjects:
Animals
Antibodies
Aorta
beta Catenin - metabolism
Biotechnology
Cardiovascular diseases
Cell membranes
Collagen
Collagen - metabolism
Endocytosis
Endocytosis - genetics
Extracellular matrix
Extracellular signal-regulated kinase
Fibroblasts
Fibrosis
Fluorescent dyes
Fluorescent indicators
Heart
Kinases
Laboratory animals
MAP Kinase Signaling System - genetics
Membrane proteins
Mice
Peptidase
Peptidases
Protease Inhibitors - pharmacology
Proteins
Receptor density
Receptors
Secretion
Serpin E2 - metabolism
Serpin E2 - pharmacology
Signal transduction
Signal Transduction - genetics
Signaling
U-Plasminogen activator
Urokinase
β-Catenin
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Summary:Cardiac fibrosis is one of the common pathological processes in many cardiovascular diseases characterized by excessive extracellular matrix deposition. SerpinE2 is a kind of protein that inhibits peptidase in extracellular matrix and up-regulated tremendously in mouse model of cardiac fibrosis induced by pressure-overloaded via transverse aortic constriction (TAC) surgery. However, its effect on cardiac fibroblasts (CFs), collagen secretion and the underlying mechanism remains unclear. In this study, DyLight® 488 green fluorescent dye or His-tagged proteins were used to label the exogenous serpinE2 protein. It was showed that extracellular serpinE2 translocated into CFs by low-density lipoprotein receptor-related protein 1 (LRP1) and urokinase plasminogen activator receptor (uPAR) of cell membrane through endocytosis. Knockdown of LRP1 or uPAR reduced the level of serpinE2 in CFs and down-regulated the collagen expression. Inhibition of the endocytosis of serpinE2 could inhibit ERK1/2 and β-catenin signaling pathways and subsequently attenuated collagen secretion. Knockdown of serpinE2 attenuates cardiac fibrosis in TAC mouse. We conclude that serpinE2 could be translocated into cardiac fibroblasts due to endocytosis through directly interact with the membrane protein LRP1 and uPAR, and this process activated the ERK1/2, β-catenin signaling pathways, consequently promoting collagen production.
ISSN:1449-2288
1449-2288
DOI:10.7150/ijbs.67726