Apixaban attenuates ischemia-induced myocardial fibrosis by inhibition of Gq/PKC signaling

Shi, Guiliang; Yang, Xiangjun; Pan, Min; Sun, Jianhui; Ke, Haiyan; Zhang, Chi; Geng, Hao

doi:10.1016/j.bbrc.2018.04.071

Cited by 7 publications

(8 citation statements)

References 19 publications

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“…However, in contrast to our expectations, we did not observe any changes in protein levels for PAR1 protein, nor did we detect differences in the activation of the AKT and ERK 1/2 signal transduction pathways downstream of PAR1 [ 48 ]. These findings are in consistence with a previous study [ 49 ] in which PAR1 protein expression did not differ at 12 weeks after MI induction or apixaban treatment. Moreover, it has been previously published that upregulated AKT exerts cardioprotective effects in models of preconditioning resulting in limiting infarct size [ 50 , 51 ].…”

Section: Discussionmentioning

confidence: 99%

“…Despite strengths related to the direct measures of cardiac structure, function and other haematological parameters, our study does have limitations. First, in accordance with the previous study [ 49 ], we did not observe changes in PAR1 protein levels in post-MI HF model. Furthermore, the activity of downstream signalling pathways of the PAR1 was not increased after MI and apixaban did not alter this.…”

Section: Study Limitationsmentioning

confidence: 99%

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Factor Xa Inhibition with Apixaban Does Not Influence Cardiac Remodelling in Rats with Heart Failure After Myocardial Infarction

Yurista

Silljé

Nijholt

et al. 2020

Cardiovasc Drugs Ther

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Background Heart failure (HF) is considered to be a prothrombotic condition and it has been suggested that coagulation factors contribute to maladaptive cardiac remodelling via activation of the protease-activated receptor 1 (PAR1). We tested the hypothesis that anticoagulation with the factor Xa (FXa) inhibitor apixaban would ameliorate cardiac remodelling in rats with HF after myocardial infarction (MI). Methods and Results Male Sprague-Dawley rats were either subjected to permanent ligation of the left ascending coronary artery (MI) or sham surgery. The MI and sham animals were randomly allocated to treatment with placebo or apixaban in the chow (150 mg/kg/day), starting 2 weeks after surgery. Cardiac function was assessed using echocardiography and histological and molecular markers of cardiac hypertrophy were assessed in the left ventricle (LV). Apixaban resulted in a fivefold increase in anti-FXa activity compared with vehicle, but no overt bleeding was observed and haematocrit levels remained similar in apixaban-and vehicle-treated groups. After 10 weeks of treatment, LV ejection fraction was 42 ± 3% in the MI group treated with apixaban and 37 ± 2 in the vehicle-treated MI group (p > 0.05). Both vehicle-and apixaban-treated MI groups also displayed similar degrees of LV dilatation, LV hypertrophy and interstitial fibrosis. Histological and molecular markers for pathological remodelling were also comparable between groups, as was the activity of signalling pathways downstream of the PAR1 receptor. Conclusion FXa inhibition with apixaban does not influence pathological cardiac remodelling after MI. These data do not support the use of FXa inhibitor in HF patients with the aim to amend the severity of HF.

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Section: Discussionmentioning

confidence: 99%

Section: Study Limitationsmentioning

confidence: 99%

Factor Xa Inhibition with Apixaban Does Not Influence Cardiac Remodelling in Rats with Heart Failure After Myocardial Infarction

Yurista

Silljé

Nijholt

et al. 2020

Cardiovasc Drugs Ther

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“…Further, integrin 1β is capable of promoting angiogenesis by mediating human endothelial cell attachment and migration 40 and is found to be able to integrate complexes that functions as a receptor to several collagen types 43 . In this matter, PAR 1 activation is intrinsically related to an increase in collagen deposition in fibroblasts 44 , 45 and, therefore, enhancing adhesion when integrin β1 is present in the substrate 46 , 47 .…”

Section: Discussionmentioning

confidence: 99%

Osteogenesis in human periodontal ligament stem cell sheets is enhanced by the protease-activated receptor 1 (PAR1) in vivo

Alves

Gasparoni

Balzarini

et al. 2022

Sci Rep

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Human periodontal ligament stem cells (PDLSCs) have been studied as a promising strategy in regenerative approaches. The protease-activated receptor 1 (PAR 1 ) plays a key role in osteogenesis and has been shown to induce osteogenesis and increase bone formation in PDLSCs. However, little is known about its effects when activated in PDLSCs as a cell sheet construct and how it would impact bone formation as a graft in vivo. Here, PDLSCs were obtained from 3 patients. Groups were divided into control, osteogenic medium and osteogenic medium + PAR 1 activation by TFLLR-NH2 peptide. Cell phenotype was determined by flow cytometry and immunofluorescence. Calcium deposition was quantified by Alizarin Red Staining. Cell sheet microstructure was analyzed through light, scanning electron microscopy and histology and transplanted to Balb/c nude mice. Immunohistochemistry for bone sialoprotein (BSP), integrin β1 and collagen type 1 and histological stains (H&E, Van Giesson, Masson’s Trichrome and Von Kossa) were performed on the ex-vivo mineralized tissue after 60 days of implantation in vivo . Ectopic bone formation was evaluated through micro-CT. PAR 1 activation increased calcium deposition in vitro as well as BSP, collagen type 1 and integrin β1 protein expression and higher ectopic bone formation (micro-CT) in vivo.

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“…Rivaroxaban treatment also inhibited FXa-mediated phosphorylation of NF-κB p65 and STAT3, which are important mediators of myofibroblast differentiation and fibrosis development ( 54 ). In the myocardial ischemia (MI)-induced fibrosis model, expression of collagen 1a1 and collagen 3a1 was significantly decreased after a high dosage of direct FXa inhibitor apixaban which indicates the efficacy of apixaban in attenuating MI-induced fibrosis ( 100 ). In unilateral ureteral obstruction (UUO) mice, which is the renal tubulointerstitial model, edoxaban treatment attenuated renal interstitial macrophage infiltration and release of inflammatory cytokines.…”

Section: Anticoagulants In Organ Fibrosismentioning

confidence: 99%

The Therapeutic Potential of Anticoagulation in Organ Fibrosis

Park

Song

et al. 2022

Front. Med.

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Fibrosis, also known as organ scarring, describes a pathological stiffening of organs or tissues caused by increased synthesis of extracellular matrix (ECM) components. In the past decades, mounting evidence has accumulated showing that the coagulation cascade is directly associated with fibrotic development. Recent findings suggest that, under inflammatory conditions, various cell types (e.g., immune cells) participate in the coagulation process causing pathological outcomes, including fibrosis. These findings highlighted the potential of anticoagulation therapy as a strategy in organ fibrosis. Indeed, preclinical and clinical studies demonstrated that the inhibition of blood coagulation is a potential intervention for the treatment of fibrosis across all major organs (e.g., lung, liver, heart, and kidney). In this review, we aim to summarize our current knowledge on the impact of components of coagulation cascade on fibrosis of various organs and provide an update on the current development of anticoagulation therapy for fibrosis.

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Apixaban attenuates ischemia-induced myocardial fibrosis by inhibition of Gq/PKC signaling

Cited by 7 publications

References 19 publications

Factor Xa Inhibition with Apixaban Does Not Influence Cardiac Remodelling in Rats with Heart Failure After Myocardial Infarction

Factor Xa Inhibition with Apixaban Does Not Influence Cardiac Remodelling in Rats with Heart Failure After Myocardial Infarction

Osteogenesis in human periodontal ligament stem cell sheets is enhanced by the protease-activated receptor 1 (PAR1) in vivo

The Therapeutic Potential of Anticoagulation in Organ Fibrosis

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