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Int J Biol Sci 2022; 18(16):6008-6019. doi:10.7150/ijbs.67726 This issue Cite

Research Paper

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

Chao Li1*, Li-fang Lv1,2*, Mu-ge Qi-Li1,3, Rui Yang1, Yu-jing Wang1, Shuang-shuang Chen1, Ming-xiu Zhang1, Tian-yu Li1, Tong Yu1, Yu-hong Zhou1, Hai-hai Liang1,4, Hong-li Shan5✉, Xue-lian Li1✉

1. Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, P. R. China.
2. The Centre of Functional Experiment Teaching, School of Basic Medicine, Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China.
3. Department of Pharmacy, Sunshine Union Hospital, Shandong Weifang, China.
4. Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, 150081, China.
5. Shanghai Frontiers Science Research Center for Druggability of Cardiovascular Noncoding RNA, Institute for Frontier Medical Technology, Shanghai University of Engineering Science, Shanghai, 201620, China.
*These authors contributed equally to this work.

✉ Corresponding authors: Xue-lian Li and Hong-li Shan. Xue-lian Li: orcid.org/0000-0001-9043-8580; Department of Pharmacology, College of Pharmacy, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin 150081, (PR China). E-mail: lixue More

Citation:
Li C, Lv Lf, Qi-Li Mg, Yang R, Wang Yj, Chen Ss, Zhang Mx, Li Ty, Yu T, Zhou Yh, Liang Hh, Shan Hl, Li Xl. Endocytosis of Peptidase Inhibitor SerpinE2 promotes Myocardial Fibrosis through activating ERK1/2 and β-catenin Signaling Pathways. Int J Biol Sci 2022; 18(16):6008-6019. doi:10.7150/ijbs.67726. https://www.ijbs.com/v18p6008.htm
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Abstract

Graphic abstract

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.

Keywords: Cardiac Fibrosis, SerpinE2, Endocytosis, ERK1/2, β-catenin signaling

Citation styles

APA
Li, C., Lv, L.f., Qi-Li, M.g., Yang, R., Wang, Y.j., Chen, S.s., Zhang, M.x., Li, T.y., Yu, T., Zhou, Y.h., Liang, H.h., Shan, H.l., Li, X.l. (2022). Endocytosis of Peptidase Inhibitor SerpinE2 promotes Myocardial Fibrosis through activating ERK1/2 and β-catenin Signaling Pathways. International Journal of Biological Sciences, 18(16), 6008-6019. https://doi.org/10.7150/ijbs.67726.

ACS
Li, C.; Lv, L.f.; Qi-Li, M.g.; Yang, R.; Wang, Y.j.; Chen, S.s.; Zhang, M.x.; Li, T.y.; Yu, T.; Zhou, Y.h.; Liang, H.h.; Shan, H.l.; Li, X.l. Endocytosis of Peptidase Inhibitor SerpinE2 promotes Myocardial Fibrosis through activating ERK1/2 and β-catenin Signaling Pathways. Int. J. Biol. Sci. 2022, 18 (16), 6008-6019. DOI: 10.7150/ijbs.67726.

NLM
Li C, Lv Lf, Qi-Li Mg, Yang R, Wang Yj, Chen Ss, Zhang Mx, Li Ty, Yu T, Zhou Yh, Liang Hh, Shan Hl, Li Xl. Endocytosis of Peptidase Inhibitor SerpinE2 promotes Myocardial Fibrosis through activating ERK1/2 and β-catenin Signaling Pathways. Int J Biol Sci 2022; 18(16):6008-6019. doi:10.7150/ijbs.67726. https://www.ijbs.com/v18p6008.htm

CSE
Li C, Lv Lf, Qi-Li Mg, Yang R, Wang Yj, Chen Ss, Zhang Mx, Li Ty, Yu T, Zhou Yh, Liang Hh, Shan Hl, Li Xl. 2022. Endocytosis of Peptidase Inhibitor SerpinE2 promotes Myocardial Fibrosis through activating ERK1/2 and β-catenin Signaling Pathways. Int J Biol Sci. 18(16):6008-6019.

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