Endocytosis of Peptidase Inhibitor SerpinE2 promotes Myocardial Fibrosis through activating ERK1/2 and β-catenin Signaling Pathways.
Endocytosis of Peptidase Inhibitor SerpinE2 promotes Myocardial Fibrosis through activating ERK1/2 and β-catenin Signaling Pathways.
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肽酶抑制剂 SerpinE2 的内吞作用通过激活 ERK1/2 和 β-catenin 信号通路促进心肌纤维化。
DOI：
10.7150/ijbs.67726
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发表时间：
2022
影响因子：
9.2
通讯作者：
Li XL
中科院分区：
文献类型：
--
作者：
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
心脏纤维化是许多心血管疾病的共同病理过程之一，其特征是细胞外基质过度沉积。SerpinE 2是一种抑制细胞外基质中肽酶的蛋白质，在压力超负荷的主动脉缩窄术（transverse aortic constriction，TAC）诱导的小鼠心肌纤维化模型中表达显著上调。然而，其对心脏成纤维细胞（CFs），胶原分泌的影响及其机制尚不清楚。在本研究中，使用DyLight® 488绿色荧光染料或His标记的蛋白质来标记外源丝氨酸蛋白酶抑制剂E2蛋白。结果表明，细胞外的serpinE 2通过细胞膜上的低密度脂蛋白受体相关蛋白1（LRP 1）和尿激酶型纤溶酶原激活物受体（uPAR）的内吞作用进入CFs。敲低LRP 1或uPAR可降低CFs中serpinE 2的表达，下调胶原的表达。抑制SerpinE 2的内吞作用可以抑制ERK 1/2和β-catenin信号通路，从而减弱胶原分泌。serpinE 2的敲低减轻TAC小鼠的心脏纤维化结论：serpinE 2可通过与膜蛋白LRP 1和uPAR相互作用，通过胞吞作用进入心肌成纤维细胞，激活ERK 1/2、β-catenin信号通路，促进胶原合成。
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.
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影响因子：
3.7
作者：
Santoro A;Conde J;Scotece M;Abella V;Lois A;Lopez V;Pino J;Gomez R;Gomez-Reino JJ;Gualillo O
通讯作者：
Gualillo O
影响因子：
11.2
作者：
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影响因子：
7.8
作者：
Alshafie, Walaa;Francis, Vincent;McPherson, Peter S.
通讯作者：
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影响因子：
4.8
作者：
Crisp, RJ;Knauer, DJ;Knauer, MF
通讯作者：
Knauer, MF
影响因子：
6.7
作者：
Kozlova, Nina;Jensen, Jan K.;Kietzmann, Thomas
通讯作者：
Kietzmann, Thomas