Dataset Information

Palmdelphin Deficiency Evokes NF-κB Signaling in Valvular Endothelial Cells and Aggravates Aortic Valvular Remodeling.

ABSTRACT: Palmd-deficient mice of advanced age manifest increased aortic valve peak velocity, thickened aortic valve leaflets, and excessive extracellular matrix deposition, which are key features of calcific aortic valve disease. PALMD is predominantly expressed in endothelial cells of aortic valves, and PALMD-silenced valvular endothelial cells are prone to oscillatory shear stress-induced endothelial-to-mesenchymal transition. Mechanistically, PALMD is associated with TNFAIP3 interaction protein 1, a binding protein of TNFAIP3 and IKBKG in NF-κB signaling. Loss of PALMD impairs TNFAIP3-dependent deubiquitinating activity and promotes the ubiquitination of IKBKG and subsequent NF-κB activation. Adeno-associated virus-mediated PALMD overexpression ameliorates aortic valvular remodeling in mice with calcific aortic valve disease, indicating protection.

SUBMITTER: Han Y

PROVIDER: S-EPMC10714178 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Palmdelphin Deficiency Evokes NF-κB Signaling in Valvular Endothelial Cells and Aggravates Aortic Valvular Remodeling.

Han Yingchun Y Zhang Jichao J Yang Zhao Z Jian Wen W Zhu Yuexin Y Gao Shijuan S Liu Yan Y Li Yingkai Y He Songyuan S Zhang Congcong C Li Yang Y You Bin B Liu Jinghua J Du Jie J

JACC. Basic to translational science 20230830 11

<i>Palmd</i>-deficient mice of advanced age manifest increased aortic valve peak velocity, thickened aortic valve leaflets, and excessive extracellular matrix deposition, which are key features of calcific aortic valve disease. PALMD is predominantly expressed in endothelial cells of aortic valves, and PALMD-silenced valvular endothelial cells are prone to oscillatory shear stress-induced endothelial-to-mesenchymal transition. Mechanistically, PALMD is associated with TNFAIP3 interaction protein ...[more]

PMID: 38093741

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Project description:BackgroundThe incidence of diabetic kidney disease (DKD) continues to rapidly increase, with limited available treatment options. One of the hallmarks of DKD is persistent inflammation, but the underlying molecular mechanisms of early diabetic kidney injury remain poorly understood. C-X-C chemokine receptor 2 (CXCR2), plays an important role in the progression of inflammation-related vascular diseases and may bridge between glomerular endothelium and persistent inflammation in DKD.MethodsMultiple methods were employed to assess the expression levels of CXCR2 and its ligands, as well as renal inflammatory response and endothelial glycocalyx shedding in patients with DKD. The effects of CXCR2 on glycocalyx shedding, and persistent renal inflammation was examined in a type 2 diabetic mouse model with Cxcr2 knockout specifically in endothelial cells (DKD-Cxcr2 eCKO mice), as well as in glomerular endothelial cells (GECs), cultured in high glucose conditions.ResultsCXCR2 was associated with early renal decline in DKD patients, and endothelial-specific knockout of CXCR2 significantly improved renal function in DKD mice, reduced inflammatory cell infiltration, and simultaneously decreased the expression of proinflammatory factors and chemokines in renal tissue. In DKD conditions, glycocalyx shedding was suppressed in endothelial Cxcr2 knockout mice compared to Cxcr2 L/L mice. Modulating CXCR2 expression also affected high glucose-induced inflammation and glycocalyx shedding in GECs. Mechanistically, CXCR2 deficiency inhibited the activation of NF-κB signaling, thereby regulating inflammation, restoring the endothelial glycocalyx, and alleviating DKD.ConclusionsTaken together, under DKD conditions, activation of CXCR2 exacerbates inflammation through regulation of the NF-κB pathway, leading to endothelial glycocalyx shedding and deteriorating renal function. Endothelial CXCR2 deficiency has a protective role in inflammation and glycocalyx dysfunction, suggesting its potential as a promising therapeutic target for DKD treatment.

Project description:Myocardial infarction (MI), the leading cause of death among patients with cardiovascular diseases, is characterized by acute cardiac muscle injury due to severe impairment of the coronary blood supply, which may lead to cardiogenic shock and cardiac arrest. Particularly interesting new cysteine histidine rich 1 (PINCH1) protein, a key component of the integrin signaling pathway, interacts with several proteins and serves a vital role in numerous cellular processes, including cytoskeleton remodeling, cell proliferation and cell migration. To investigate the role of PINCH1 in heart injury in the present study, PINCH1 was knocked out in the myocardial tissue of mice (age, 18 weeks) to induce MI. In addition, cell viability, migration and apoptosis, as well as the expression levels of NF-κB-associated proteins were determined in murine HL1 cardiomyocytes with a conditional PINCH1 shRNA using Cell Counting Kit-8, Transwell, flow cytometry and western blot assays, respectively. Furthermore, the cardiac expansion and myocardial fibrosis in PINCH1 knockout mice was investigated in vivo by performing morphological and histological examinations. Additionally, the murine ventricular myocardial ultrastructure was evaluated using an electron microscope, and the cardiomyocyte apoptotic rate and expression levels of NF-κB-related proteins were determined using TUNEL and western blot assays, respectively. The results showed that the apoptotic rate in the in vivo PINCH1 knockdown group was significantly increased. In addition, the protein expression levels of NF-κB signaling pathway-related proteins, including NF-κB, myeloid differentiation factor 88, TNF-α and caspase-3, were significantly increased in the in vivo PINCH1 knockdown group compared with the wild-type group, but the protein expression of MMP2 and MMP9 were the opposite. Overall, the in vitro and in vivo results revealed that PINCH1 knockout in mice significantly aggravated MI via the NF-κB signaling pathway.

Project description:BackgroundMacrophage infiltration and polarization are integral to the progression of heart failure and cardiac fibrosis after ischemia/reperfusion (IR). Interleukin 34 (IL-34) is an inflammatory regulator related to a series of autoimmune diseases. Whether IL-34 mediates inflammatory responses and contributes to cardiac remodeling and heart failure post-IR remains unclear.MethodsIL-34 knock-out mice were used to determine the role of IL-34 on cardiac remodeling after IR surgery. Then, immunofluorescence, flow cytometry assays, and RNA-seq analysis were performed to explore the underlying mechanisms of IL-34-induced macrophage recruitment and polarization, and further heart failure after IR.FindingsBy re-analyzing single-cell RNA-seq and single-nucleus RNA-seq data of murine and human ischemic hearts, we showed that IL-34 expression was upregulated after IR. IL-34 knockout mitigated cardiac remodeling, cardiac dysfunction, and fibrosis after IR and vice versa. RNA-seq analysis revealed that IL-34 deletion correlated negatively with immune responses and chemotaxis after IR injury. Consistently, immunofluorescence and flow cytometry assays demonstrated that IL-34 deletion attenuated macrophage recruitment and CCR2+ macrophage polarization. Mechanistically, IL-34 deficiency repressed both the canonical and noncanonical NF-κB signaling pathway, leading to marked reduction of P-IKKβ and P-IκBα kinase levels; downregulation of NF-κB p65, RelB, and p52 expression, which drove the decline in chemokine CCL2 expression. Finally, IL-34 and CCL2 levels were increased in the serum of acute coronary syndrome patients, with a positive correlation between circulating IL-34 and CCL2 levels in clinical patients.InterpretationIn conclusion, IL-34 sustains NF-κB pathway activation to elicit increased CCL2 expression, which contributes to macrophage recruitment and polarization, and subsequently exacerbates cardiac remodeling and heart failure post-IR. Strategies targeting IL-34-centered immunomodulation may provide new therapeutic approaches to prevent and reverse cardiac remodeling and heart failure in clinical MI patients after percutaneous coronary intervention.FundingThis study was supported by the National Nature Science Foundation of China (81670352 and 81970327 to R T, 82000368 to Q F).

Dataset Information

Palmdelphin Deficiency Evokes NF-κB Signaling in Valvular Endothelial Cells and Aggravates Aortic Valvular Remodeling.

Publications

Palmdelphin Deficiency Evokes NF-κB Signaling in Valvular Endothelial Cells and Aggravates Aortic Valvular Remodeling.

Similar Datasets

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