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

Li, Chao; Lv, Le; Qili, Muge; Yang, Rui; Wang, Yujing; Chen, Shuangshuang; Zhang, Ming-Xiu; Li, Tianyu; Yu, Tong; Zhou, Yuhong; Liang, Haihai; Shan, Hongli; Li, Xuelian

doi:10.7150/ijbs.67726

Cited by 9 publications

(2 citation statements)

References 32 publications

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“…Immunoreactive protein bands were visualized using ECL reagent. The representative image for each group was selected to show the average or median level of the group based upon the mean value 34 .…”

Section: Methodsmentioning

confidence: 99%

Serine/threonine kinase 3 promotes oxidative stress and mitochondrial damage in septic cardiomyopathy through inducing Kelch-like ECH-associated protein 1 phosphorylation and nuclear factor erythroid 2-related factor 2 degradation

Zhu¹,

Dai²,

Liu³

et al. 2023

Int. J. Biol. Sci.

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Serine/threonine kinases (STK3) is a core component of the Hippo pathway and modulates oxidative stress and inflammatory responses in cardiovascular diseases. However, its potential role in septic cardiomyopathy remains undefined. STK3-mediated phosphorylation of Kelch-like ECH-associated protein 1 (KEAP1) was shown to suppress antioxidant gene transcription controlled by nuclear factor erythroid 2-related factor 2 (Nrf2) in macrophages. To explore whether STK3 induces KEAP1-mediated suppression of Nrf2 in septic cardiomyopathy, wild-type and global STK3 knockout (STK3 -/- ) mice were treated with LPS. LPS treatment upregulated cardiac STK3 expression. STK3 deletion attenuated myocardial inflammation and cardiomyocyte death, and improved myocardial structure and function. In LPS-challenged HL-1 cardiomyocytes, shRNA-mediated STK3 knockdown normalized mitochondrial membrane potential and ATP production, attenuated apoptosis, and rescued antioxidant gene expression by preventing Nrf2 downregulation. Co-IP, docking analysis, western blotting, and immunofluorescence assays further showed that STK3 binds and phosphorylates KEAP1, promoting Nrf2 downregulation. Accordingly, transfection of phosphodefective KEAP1 mutant protein in cardiomyocyte restored Nrf2 expression and mitochondrial performance upon LPS, while expression of a phosphomimetic KEAP1 mutant abolished the mitochondria-protective and pro-survival effects of STK3 deletion. These findings suggest that STK3 upregulation contributes to septic cardiomyopathy by phosphorylating KEAP1 to promote Nrf2 degradation and suppression of the antioxidant response.

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Section: Methodsmentioning

confidence: 99%

Serine/threonine kinase 3 promotes oxidative stress and mitochondrial damage in septic cardiomyopathy through inducing Kelch-like ECH-associated protein 1 phosphorylation and nuclear factor erythroid 2-related factor 2 degradation

Zhu¹,

Dai²,

Liu³

et al. 2023

Int. J. Biol. Sci.

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“…It has been speculated that this paradox is related to the TME ( Smirnova et al, 2016 ). Serpin E2 has also been shown to activate ERK1/2 and β-catenin signaling pathways by interacting with LRP-1 and uPAR, which in turn promotes collagen production in fibroblasts and induces cardiac fibrosis ( Li et al, 2022 ; Kmiotek-Wasylewska et al, 2023 ). However, disease occurrence and development involves complex processes, and there may be many protein changes or protein interactions that have yet to be discovered.…”

Section: Roles Of Serpin E2 In Pathological Processesmentioning

confidence: 99%

Serpin peptidase inhibitor, clade E, member 2 in physiology and pathology: recent advancements

Wu,

Yang,

Zhang

et al. 2024

Front. Mol. Biosci.

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Serine protease inhibitors (serpins) are the most numerous and widespread multifunctional protease inhibitor superfamily and are expressed by all eukaryotes. Serpin E2 (serpin peptidase inhibitor, clade E, member 2), a member of the serine protease inhibitor superfamily is a potent endogenous thrombin inhibitor, mainly found in the extracellular matrix and platelets, and expressed in numerous organs and secreted by many cell types. The multiple functions of serpin E2 are mainly mediated through regulating urokinase-type plasminogen activator (uPA, also known as PLAU), tissue-type plasminogen activator (tPA, also known as PLAT), and matrix metalloproteinase activity, and include hemostasis, cell adhesion, and promotion of tumor metastasis. The importance serpin E2 is clear from its involvement in numerous physiological and pathological processes. In this review, we summarize the structural characteristics of the Serpin E2 gene and protein, as well as its roles physiology and disease.

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Anti-inflammatory, Anti-fibrotic and Pro-cardiomyogenic Effects of Genetically Engineered Extracellular Vesicles Enriched in miR-1 and miR-199a on Human Cardiac Fibroblasts

Kmiotek-Wasylewska,

Bobis-Wozowicz,

Karnas

et al. 2023

Stem Cell Rev and Rep

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Rationale Emerging evidence indicates that stem cell (SC)- derived extracellular vesicles (EVs) carrying bioactive miRNAs are able to repair damaged or infarcted myocardium and ameliorate adverse remodeling. Fibroblasts represent a major cell population responsible for scar formation in the damaged heart. However, the effects of EVs on cardiac fibroblast (CFs) biology and function has not been investigated. Objective To analyze the biological impact of stem cell-derived EVs (SC-EVs) enriched in miR-1 and miR-199a on CFs and to elucidate the underlying molecular mechanisms. Methods and Results Genetically engineered human induced pluripotent stem cells (hiPS) and umbilical cord-derived mesenchymal stem cells (UC-MSCs) expressing miR-1 or miR-199a were used to produce miR-EVs. Cells and EVs were thoughtfully analyzed for miRNA expression using RT-qPCR method. Both hiPS-miRs-EVs and UC-MSC-miRs-EVs effectively transferred miRNAs to recipient CFs, however, hiPS-miRs-EVs triggered cardiomyogenic gene expression in CFs more efficiently than UC-MSC-miRs-EVs. Importantly, hiPS-miR-1-EVs exhibited cytoprotective effects on CFs by reducing apoptosis, decreasing levels of pro-inflammatory cytokines (CCL2, IL-1β, IL-8) and downregulating the expression of a pro-fibrotic gene – α-smooth muscle actin (α-SMA). Notably, we identified a novel role of miR-199a-3p delivered by hiPS-EVs to CFs, in triggering the expression of cardiomyogenic genes (NKX2.5, TNTC, MEF2C) and ion channels involved in cardiomyocyte contractility (HCN2, SCN5A, KCNJ2, KCND3). By targeting SERPINE2, miR-199a-3p may reduce pro-fibrotic properties of CFs, whereas miR-199a-5p targeted BCAM and TSPAN6, which may be implicated in downregulation of inflammation. Conclusions hiPS-EVs carrying miR-1 and miR-199a attenuate apoptosis and pro-fibrotic and pro-inflammatory activities of CFs, and increase cardiomyogenic gene expression. These finding serve as rationale for targeting fibroblasts with novel EV-based miRNA therapies to improve heart repair after myocardial injury. Graphical Abstract

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

Cited by 9 publications

References 32 publications

Serine/threonine kinase 3 promotes oxidative stress and mitochondrial damage in septic cardiomyopathy through inducing Kelch-like ECH-associated protein 1 phosphorylation and nuclear factor erythroid 2-related factor 2 degradation

Serine/threonine kinase 3 promotes oxidative stress and mitochondrial damage in septic cardiomyopathy through inducing Kelch-like ECH-associated protein 1 phosphorylation and nuclear factor erythroid 2-related factor 2 degradation

Serpin peptidase inhibitor, clade E, member 2 in physiology and pathology: recent advancements

Anti-inflammatory, Anti-fibrotic and Pro-cardiomyogenic Effects of Genetically Engineered Extracellular Vesicles Enriched in miR-1 and miR-199a on Human Cardiac Fibroblasts

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