Journal
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
Volume 18, Issue 15, Pages 6008-6019Publisher
IVYSPRING INT PUBL
DOI: 10.7150/ijbs.67726
Keywords
Cardiac Fibrosis; SerpinE2; Endocytosis; ERK1; 2; ?-catenin signaling
Categories
Funding
- National Natural Science Foundation of China [81870211, 81872863, 81900225, 81770284]
- 2020 young innovative talents training Program of Heilongjiang Normal university [UNPYSCT-2020166]
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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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