BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
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2025
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IF 4.2
Yongpeng Fang,Xudong Niu,Weifang Zhao,Huali Zhang
Myocardial ischemia/reperfusion (I/R) injury is a major cause of various adverse cardiovascular outcomes associated with excessive mitophagy and cardiomyocyte ferroptosis. Paired-related homeobox 1 (PRRX1) is a transcriptional factor involved in cardiovascular injury. However, whether and how PRRX1 regulates excessive mitophagy and cardiomyocyte ferroptosis during myocardial I/R injury remains unclear. Oxygen-glucose deprivation and reperfusion (OGD/R)-treated AC16 cardiomyocytes and myocardial I/R-induced rats were used as in vitro and in vivo models. Our results showed that PRRX1 expression was upregulated in AC16 cells after OGD/R treatment. PRRX1 silencing mitigated OGD/R-induced excessive mitophagy by increasing the mitochondrial membrane potential, adenosine triphosphate and p62 levels, and reducing LC3 II/I level in AC16 cells. In addition, PRRX1 knockdown attenuated OGD/R-induced lactate dehydrogenase (LDH) release and cardiomyocyte ferroptosis by decreasing reactive oxygen species, Fe 2+ and acyl-CoA synthetase long-chain family member 4 (ACSL4) levels, and increasing glutathione (GSH) and glutathione peroxidase 4 (GPX4) levels. Furthermore, PRRX1 transcriptionally promoted FK506 binding protein 5 (FKBP5), and increased p38 MAPK activation in AC16 cells. FKBP5 overexpression reversed the effects of PRRX1 silencing on excessive mitophagy and cardiomyocyte ferroptosis in OGD/R-treated AC16 cells. These effects were mitigated by a p38 MAPK inhibitor. Finally, PRRX1 downregulation mitigated myocardial I/R injury by reducing heart infarction and creatine kinase-myocardial band (CK-MB) levels in rat models. These findings demonstrate that PRRX1 silencing attenuates OGD/R-induced excessive mitophagy and cardiomyocyte ferroptosis by decreasing FKBP5 expression and inactivating p38 MAPK signaling, indicating the cardioprotective potential of PRRX1 silencing in myocardial I/R injury.
研究领域:
心血管生物学
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分子医学
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细胞生物学
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DOI
PubMed
高影响因子
Frontiers in Bioscience-Landmark
·
2024
·Vol. 29
·期 9
·325
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IF 3.3
Ziwei Guo,Sixu Bao,Zehui Shi,Xuejiao Li,Peijin Li,Bin Zhong,Ming Zhang,Qiyong Wu
Background: Platelets have the hemostatic function, and their aberrant activation is associated with occlusive thrombus formation. Plasma exosomes are rich in platelets containing ubiquitin-specific peptidase 15 (USP15). Herein, we aim to explore the effect of USP15 on thrombosis, as well as expounding whether USP15 acts as an upstream target of FK506 binding protein 5 (FKBP5) to regulate occlusive thrombus formation. Methods: Washed human platelets were treated with thrombin for measurement of USP15 and FKBP5 expressions. USP15 loss/gain-of-function variant in HEK293 cells was performed by cell transfection, and the interaction between USP15 and FKBP5 was examined using immunoprecipitation and ubiquitination assays. Mice with USP15-knockout platelets (Plt USP15-/-) were modeled, and subjected to calculation of bleeding time, artery thrombosis imaging and clot retraction assay. FKBP5 expression and the inhibitor of nuclear factor kappa B kinase subunit epsilon (IKBKE)/phosphatidylinositol 3-kinase (PI3K)/Rap1 pathway in wild-type and Plt USP15-/- mice-derived platelets were detected using Western blot. The activation of αIIbβ3 in washed platelets was analyzed using flow cytometry. Results: USP15 and FKBP5 expressions were upregulated in platelets after thrombin treatment. Following transfection of USP15 knockdown and USP15 overexpression plasmids into HEK293 cells, FKBP5 protein expression was downregulated by USP15 knockdown while being upregulated by USP15 overexpression. USP15 bound to FKBP5 and protected FKBP5 against ubiquitination. Knockdown of platelet USP15 prolonged bleeding time, inhibited arterial thrombosis and delayed clot retraction in mice. Knockdown of platelet USP15 also decreased protein expressions of FKBP5, IKBKE and Rap1, p-PI3K/PI3K ratio, and activation of αIIbβ3 in mice. Conclusion: USP15 knockdown in platelets affects thrombosis in mice by promoting the instability of FKBP5 to repress the activation of IKBKE/PI3K/Rap1 pathway-mediated αIIbβ3.
研究领域:
血液学
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分子生物学
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血栓
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细胞信号传导
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DOI
PubMed
高影响因子
JOURNAL OF INTERFERON AND CYTOKINE RESEARCH
·
2025
·
IF 1.8
Jian Li,Anwaier Apizi,Tingting Song,Paiheriding Kamilijiang,Xiangyou Yu,Ruifeng Chai,Zhaoxia Yu
Background: The pro-apoptotic and pro-inflammatory effects of FK506 binding protein 5 (FKBP5) in sepsis-induced acute kidney injury have been previously reported. However, its biological functions and underlying mechanisms in regulating sepsis-induced intestinal injury remain elusive. Therefore, this study aimed to explore the effects of FKBP5 on sepsis-induced intestinal injury.Methods: A mouse model of sepsis was established by cecal ligation and puncture (CLP). A cell model was established by treating Caco-2 cells with lipopolysaccharide (LPS). The impacts of FKBP5 knockdown on apoptosis, barrier integrity, inflammation, and the nuclear factor kappa B (NF-κB) signaling were evaluated in ileal tissue and Caco-2 cells.Results: FKBP5 expression was elevated in the ileal tissue in response to CLP and LPS treatments. In mice with sepsis, FKBP5 knockdown reduced cell apoptosis and regulated Bax, Bcl-2, and cleaved PARP levels. FKBP5 knockdown also reduced the levels of D-lactic acid, tumor necrosis factor alpha, interleukin (IL)-6, and IL-1β, improved intestinal histopathological damage, and enhanced the expression of zonula occludens-1 and occludin. FKBP5 knockdown also displayed protective effects in LPS-stimulated cells. FKBP5 knockdown inhibited the NF-κB signaling in CLP and LPS groups.Conclusion: Inhibition of FKBP5 alleviates inflammation and intestinal barrier dysfunction in sepsis, partially by inhibiting the NF-κB signaling.
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PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Yanan Li,Yanmei Qiu,Yunlei Yang,Yanhao Wei,Haokun Peng,Longhai Zeng,Pengcheng Li,Rentang Bi,Bo Hu
The role of microglia in blood–brain barrier (BBB) leakage and neovascularization after ischemic stroke remains unclear. Here, a post-stroke perivascular niche of microglia characterized by low expression of M2 markers and elevated glycolysis, oxidative phosphorylation (OXPHOS), and phagocytic activity is identified, which is termed stroke-activated vascular-associated microglia (stroke-VAM). It is found that Fkbp5 acts as a central regulator driving BBB disruption and impaired neovascularization through stroke-VAM. Single-nucleus RNA sequencing (snRNA-seq) analysis of Cx3cr1 Cre Fkbp5 flox/flox ( Fkbp5 cKO) mice in the ipsilateral hemisphere reveals enhanced interactions between stroke-VAM and endothelial cells, influencing signaling pathways that maintain BBB integrity and promote neovascularization. After ischemic injury, microglia in Fkbp5 cKO mice exhibits higher M2 marker expression and reduces glycolysis, OXPHOS, and phagocytosis, resulting in decreased BBB leakage and enhanced angiogenesis. Mechanistically, unbiased snRNA-seq analysis shows that the Hippo signaling pathway is altered in Fkbp5 cKO stroke-VAM. Fkbp5 inhibits Yap1 phosphorylation, facilitating its nuclear translocation. These findings provide new insights into how the perivascular microglial niche contributes to both the degradation and regeneration of cerebral vasculature, offering potential therapeutic avenues for acute ischemic stroke.
研究领域:
神经科学
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脑血管疾病
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免疫学
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分子生物学
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细胞代谢
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再生医学
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产品关联
DOI
PubMed
高影响因子
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