Cell type-specific roles of PAR1 in Coxsackievirus B3 infection

Bode, Michael F.; Schmedes, Clare M.; Egnatz, Grant J.; Bharathi, Vanthana; Hisada, Yohei; Martinez, David R.; Kawano, Tetsuya; Weithäuser, Alice; Rosenfeldt, Leah; Rauch, Ursula; Palumbo, Joseph S.; Antoniak, Silvio; Mackman, Nigel

doi:10.1038/s41598-021-93759-8

Cited by 6 publications

(5 citation statements)

References 59 publications

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“…Noteworthy, the downstream signaling pathways activated by PAR1 include MAPKs (ex. ERK1/2) and PI3K/AKT/mTOR [ 46 ] and may be associated with autophagy inhibition [ 47 ], increased proliferation, and migration [ 33 ], which may be important factors in the malignancy and invasion capacity of gliomas. Our study indicates that ConGF can interact with the glycans of MMP1 and trigger glioma cell death and autophagy.…”

Section: Resultsmentioning

confidence: 99%

Structural Prediction and Characterization of Canavalia grandiflora (ConGF) Lectin Complexed with MMP1: Unveiling the Antiglioma Potential of Legume Lectins

et al. 2022

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A glioblastoma (GBM) is a highly malignant primary brain tumor with a poor prognosis because of its invasiveness and high resistance to current therapies. In GBMs, abnormal glycosylation patterns are associated with malignancy, which allows for the use of lectins as tools for recognition and therapy. More specifically, lectins can interact with glycan structures found on the malignant cell surface. In this context, the present work aimed to investigate the antiglioma potential of ConGF, a lectin purified from Canavalia grandiflora seeds, against C6 cells. The treatment of C6 cells with ConGF impaired the mitochondrial transmembrane potential, reduced cell viability, and induced morphological changes. ConGF also induced massive autophagy, as evaluated by acridine orange (AO) staining and LC3AB-II expression, but without prominent propidium iodide (PI) labeling. The mechanism of action appears to involve the carbohydrate-binding capacity of ConGF, and in silico studies suggested that the lectin can interact with the glycan structures of matrix metalloproteinase 1 (MMP1), a prominent protein found in malignant cells, likely explaining the observed effects.

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Section: Resultsmentioning

confidence: 99%

Structural Prediction and Characterization of Canavalia grandiflora (ConGF) Lectin Complexed with MMP1: Unveiling the Antiglioma Potential of Legume Lectins

et al. 2022

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“… 20 , 22 Par1 fl/fl mice were generated as previously described and crossed with mice expressing cre recombinase under the control of the cardiomyocyte specific myosin light chain 2v promoter ( Mlc2v cre ). 23 , 24 Cardiomyocyte specific PAR1 deficient mice ( Par1 fl/fl ;Mlc2v cre ) and littermate controls ( Par1 fl/fl ) were generated. In addition, Par1 fl/fl mice were crossed with mice expressing cre recombinase under the control of the cardiac fibroblast specific tamoxifen inducible transcription factor 21 promoter ( Tcf21 creERT2 ).…”

Section: Methodsmentioning

confidence: 99%

“…In addition, Par1 fl/fl mice were crossed with mice expressing cre recombinase under the control of the cardiac fibroblast specific tamoxifen inducible transcription factor 21 promoter ( Tcf21 creERT2 ). 24 Cardiac fibroblast PAR1deficient mice ( Par1 fl/fl ;Tcf21 creERT2 ) and littermate controls ( Par1 fl/fl ) were generated. To induce cre recombinase expression in an appropriately controlled manner Par1 fl/fl ;Tcf21 creERT2 and Par1 fl/fl mice were gavaged with tamoxifen (2 mg/mouse, Sigma-Aldrich, St. Louis, MO) for 5 days.…”

Section: Methodsmentioning

confidence: 99%

Thrombin-mediated activation of PAR1 enhances doxorubicin-induced cardiac injury in mice

et al. 2023

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The chemotherapeutic drug doxorubicin is cardiotoxic and can cause irreversible heart failure. In addition to being cardiotoxic, doxorubicin also induces activation of coagulation. We determined the effect of thrombin-mediated activation of protease-activated receptor 1 (PAR1) on doxorubicin-induced cardiac injury. Administration of doxorubicin to mice resulted in significantly increased plasma prothrombin fragment 1+2, thrombin-antithrombin complexes and extracellular vesicle tissue factor activity. Importantly, mice expressing low levels of tissue factor, but not factor XII deficient mice, treated with doxorubicin had reduced plasma thrombin-antithrombin complexes compared to controls. To evaluate the role of thrombin mediated activation of PAR1, transgenic mice insensitive to thrombin (Par1R41Q) or to activated protein C (Par1R46Q) were subjected to acute and chronic models of doxorubicin-induced cardiac injury and compared to Par1 wildtype (Par1+/+) and PAR1 deficient (Par1-/-) mice. Critically, Par1R41Q and Par1-/- mice, but not Par1R46Q mice, demonstrated similar reductions in the cardiac injury marker cardiac troponin I, preserved cardiac function and reduced cardiac fibrosis compared to Par1+/+ controls after administration of doxorubicin. Further, inhibition of Gq signaling downstream of PAR1 with the small molecule inhibitor Q94 significantly preserved cardiac function in Par1+/+ but not in Par1R41Q mice subject to the acute model of cardiac injury compared to vehicle controls. In addition, mice with PAR1 deleted in either cardiomyocytes or cardiac fibroblasts demonstrated reduced cardiac injury compared to controls. Taken together, these data suggest that thrombin-mediated activation of PAR1 contributes to doxorubicin induced cardiac injury.

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“…CXCL10 is an ISG that recruits NK cells and CD3 + leukocytes to eliminate infected cells and contain the viral infection [160]. However, PAR1 activity may enhance viral replication by reducing autophagic flux [161,162]. The reduction in autophagic flux prevents the degradation of viral RNA, viral proteins, and autophagosomes, leading to an accumulation of autophagosome membranes that can be exploited as scaffolds for virus assembly [162].…”

Section: Fibroblastsmentioning

confidence: 99%

Role of Coxsackievirus B3-Induced Immune Responses in the Transition from Myocarditis to Dilated Cardiomyopathy and Heart Failure

Yip

Lai

Yang

2023

IJMS

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Dilated cardiomyopathy (DCM) is a cardiac disease marked by the stretching and thinning of the heart muscle and impaired left ventricular contractile function. While most patients do not develop significant cardiac diseases from myocarditis, disparate immune responses can affect pathological outcomes, including DCM progression. These altered immune responses, which may be caused by genetic variance, can prolong cytotoxicity, induce direct cleavage of host protein, or encourage atypical wound healing responses that result in tissue scarring and impaired mechanical and electrical heart function. However, it is unclear which alterations within host immune profiles are crucial to dictating the outcomes of myocarditis. Coxsackievirus B3 (CVB3) is a well-studied virus that has been identified as a causal agent of myocarditis in various models, along with other viruses such as adenovirus, parvovirus B19, and SARS-CoV-2. This paper takes CVB3 as a pathogenic example to review the recent advances in understanding virus-induced immune responses and differential gene expression that regulates iron, lipid, and glucose metabolic remodeling, the severity of cardiac tissue damage, and the development of DCM and heart failure.

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Cell type-specific roles of PAR1 in Coxsackievirus B3 infection

Cited by 6 publications

References 59 publications

Structural Prediction and Characterization of Canavalia grandiflora (ConGF) Lectin Complexed with MMP1: Unveiling the Antiglioma Potential of Legume Lectins

Structural Prediction and Characterization of Canavalia grandiflora (ConGF) Lectin Complexed with MMP1: Unveiling the Antiglioma Potential of Legume Lectins

Thrombin-mediated activation of PAR1 enhances doxorubicin-induced cardiac injury in mice

Role of Coxsackievirus B3-Induced Immune Responses in the Transition from Myocarditis to Dilated Cardiomyopathy and Heart Failure

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