4.7 Article

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

期刊

INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
卷 18, 期 15, 页码 6008-6019

出版社

IVYSPRING INT PUBL
DOI: 10.7150/ijbs.67726

关键词

Cardiac Fibrosis; SerpinE2; Endocytosis; ERK1; 2; ?-catenin signaling

资金

  1. National Natural Science Foundation of China [81870211, 81872863, 81900225, 81770284]
  2. 2020 young innovative talents training Program of Heilongjiang Normal university [UNPYSCT-2020166]

向作者/读者索取更多资源

In this study, the researchers found that serpinE2 can be translocated into cardiac fibroblasts through endocytosis by interacting with membrane proteins LRP1 and uPAR. This process activates the ERK1/2 and β-catenin signaling pathways, consequently promoting collagen production.
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 (R) 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 beta-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, beta-catenin signaling pathways, consequently promoting collagen production.

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