Balancing thromboembolic and bleeding risk with non-vitamin K antagonist oral anticoagulants (NOACs): A systematic review and meta-analysis on gender differences

Proietti, Marco; Cheli, Paola; Basili, Stefania; Mazurek, Michał; Lip, Gregory Y.H.

doi:10.1016/j.phrs.2017.01.004

Cited by 29 publications

(22 citation statements)

References 34 publications

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“…We find that the expression of p-JNK and p-p38 in H9c2 cells is unaffected by hypoxia after TGF-β1 and hypoxia co-treatment, which suggests that JNK and p38 are not likely to be involved in the TGF-β1-induced myofibroblast transformation in H9c2 cells. Expression of p-ERK is elevated after TGF-β1 treatment, consistent with previous findings that TGF-β1 induces lung fibroblast-to-myofibroblast conversion via ERK1/2 activation [36]. Interestingly, co-treatment with hypoxia and TGF-β1 increases the expression of p-ERK with hypoxia time, same as the effect of TGF-β1, but less than TGF-β1 treatment alone at 1 h after hypoxia co-treatment.…”

Section: Discussionsupporting

confidence: 89%

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Hypoxia Suppresses TGF-B1-Induced Cardiac Myocyte Myofibroblast Transformation by Inhibiting Smad2/3 and Rhoa Signaling Pathways

Yan

Shen

Liao

et al. 2018

Cell Physiol Biochem

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Background/Aims: Hypoxia modulation of transforming growth factor (TGF)- β-induced signaling during myofibroblast transformation is dependent on the specific cell type. The purpose of this study was to explore the effects of hypoxia on myofibroblast transformation of TGF-β1-induced cardiomyocyte H9c2 cells. Methods: H9c2 cells were cultured for intermittent hypoxia treatment and TGF-β1 treatment. α-Smooth muscle actin (α-SMA) expression was examined by western blotting and immunofluorescence after treatment. To further explore the possible mechanism for this effect, the effects of hypoxia on three early TGF-β-dependent signaling pathways, i.e. the Smad2/3, RhoA and mitogen-activated protein kinase (MAPK) pathways, were screened by western blotting. Results: Intermittent hypoxia induced TGF-β1 expression, but had no effect on α-SMA expression. Exogenous TGF-β1 alone upregulated α-SMA expression in H9c2 cells in a concentration- and time-dependent manner. α-SMA expression declined with the duration of hypoxia after intermittent hypoxia and exogenous TGF-β1 co-treatment. Phospho-JNK and phospho-p38 levels were not significantly altered after TGF-β1 and hypoxia treatment. However, levels of phospho-ERK increased after TGF-β1 treatment and continued to increase after hypoxia co-treatment. The activation of phospho-Smad2/3 and phospho-RhoA induced by TGFβ1 was significantly reduced after hypoxia co-treatment. Conclusion: Hypoxia can inhibit TGF-β1-induced H9c2 myofibroblast transformation, based on inhibition of α-SMA expression by suppressing signaling downstream of TGF-β1, Smad2/3 and RhoA. It suggested that TGF-β-mediated cardiomyocyte transformation is not involved in hypoxia-mediated fibrosis.

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Section: Discussionsupporting

confidence: 89%

“…The MAPK family is well-known for signaling in TGF-β1-induced fibrosis [36, 37]. Liu et al have demonstrated that reduction of ERK1/2 phosphorylation and Smad-mediated recruitment of transcriptional coactivators inhibits the profibrotic effects of TGF-β in cardiac fibroblasts [38].…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Suppresses TGF-B1-Induced Cardiac Myocyte Myofibroblast Transformation by Inhibiting Smad2/3 and Rhoa Signaling Pathways

Yan

Shen

Liao

et al. 2018

Cell Physiol Biochem

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“…Some of the Ang II effects are mediated by the release of several factors, including TGF-β [40] and plasminogen activator inhibitor type-1 (PAI-1) [25]. TGF-β1 induces α-SMA expression and collagen production via Erk1/2 activation, and TGF-β1 targets the GSK-3β/β-catenin pathway via Erk activation in the transition of human lung fibroblasts into myofibroblasts [41]. TGF-β induced Wnt secretion and activated the Wnt/β-catenin pathway.…”

Section: Discussionmentioning

confidence: 99%

Aspirin Reduces Cardiac Interstitial Fibrosis by Inhibiting Erk1/2-Serpine2 and P-Akt Signalling Pathways

Wang²,

Qili

et al. 2018

Cell Physiol Biochem

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Background/Aims: Cardiac interstitial fibrosis is an abnormality of various cardiovascular diseases, including myocardial infarction, hypertrophy, and atrial fibrillation, and it can ultimately lead to heart failure. However, there is a lack of practical therapeutic approaches to treat fibrosis and reverse the damage to the heart. The purpose of this study was to investigate the effect of long-term aspirin administration on pressure overload–induced cardiac fibrosis in mice and reveal the underlying mechanisms of aspirin treatment. Methods: C57BL/6 mice were subjected to transverse aortic constriction (TAC), and treated with 10 mg·kg^-1·day^-1 of aspirin for 4 weeks. Masson staining and a collagen content assay were used to detect the effects of aspirin on cardiac fibrosis in vivo and in vitro. Western blot and qRT-PCR were applied to examine the impact of aspirin on extracellular signal-regulated kinases (Erks), p-Akt/β-catenin, SerpinE2, collagen I, and collagen III levels in the mice heart. Results: Aspirin significantly suppressed the expression of α-smooth muscle actin (α-SMA; 1.19±0.19-fold) and collagen I (0.95±0.09-fold) in TAC mice. Aspirin, at doses of 100 and 1000 µM, also significantly suppressed angiotensin II-induced α-SMA and collagen I in cultured CFs. The enhanced phosphorylation of Erk1/2 caused by TAC (p-Erk1, 1.49±0.19-fold; p-Erk2, 1.96±0.68-fold) was suppressed by aspirin (p-Erk1, 1.04±0.15-fold; p-Erk2, 0.87±0.06-fold). SerpinE2 levels were suppressed via the Erk1/2 signalling pathway following treatment with aspirin (1.36±0.12-fold for TAC; 1.06±0.07-fold for aspirin+TAC). The p-Akt and β-catenin levels were also significantly inhibited in vivo and in vitro. Conclusions: Our study reveals a novel mechanism by which aspirin alleviates pressure overload-induced cardiac interstitial fibrosis in TAC mice by suppressing the p-Erk1/2 and p-Akt/β-catenin signalling pathways.

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“…A large systematic review of the available evidences from randomized trials on NOACs along with a systematic meta-analysis of the 4 phase III clinical trials was conducted by Proietti et al [ 32 ]. The aim was to investigate sex differences in stroke/SE events and major bleedings for a better assessment of major adverse outcomes according to sex, during the treatment.…”

Section: From Vka To Noacsmentioning

confidence: 99%

Female Sex as a Thromboembolic Risk Factor in the Era of Nonvitamin K Antagonist Oral Anticoagulants

Gallù

Marrone

Legramante

et al. 2020

Cardiovascular Therapeutics

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Sex-specific differences have been definitively demonstrated in cardiovascular (CV) diseases. These differences can also impact on the effects of CV therapies. Female sex is recognized as an independent predictor of thromboembolic risk, particularly in older patients. Most of strokes are due to atrial fibrillation (AF). Women affected by AF have higher stroke risk compared to men. The introduction of novel oral anticoagulants (NOACs) for long-term anticoagulation completely changed the anticoagulant therapeutic approach and follow-up of patients affected by nonvalvular atrial fibrillation (NVAF). CHA2DS2-VASc stroke risk scoring in use in the current international guidelines attributes 1 point to “female sex”. Besides, no anticoagulation is indicated for AF female patients without other risk factors. Interestingly, NOACs seem to normalize the differences between males and females both in terms of safety and efficacy, whereas residual higher stroke risk and systemic embolism persist in AF women treated with vitamin K antagonist anticoagulants VKA with optimal time in therapeutic range. Based on the CHA2DS2-VASc score, NOACs represent the preferred choice in NVAF patients. Moreover, complete evaluation of apparently lower risk factor along with concomitant clinical conditions in AF patients appears mandatory, particularly for female patients, in order to achieve the most appropriate anticoagulant treatment, either in male or in female patients. The present review was performed to review sex differences in AF-related thromboembolic risk reported in the literature and possibly highlight current knowledge gaps in prevention and management that need further research.

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Balancing thromboembolic and bleeding risk with non-vitamin K antagonist oral anticoagulants (NOACs): A systematic review and meta-analysis on gender differences

Cited by 29 publications

References 34 publications

Hypoxia Suppresses TGF-B1-Induced Cardiac Myocyte Myofibroblast Transformation by Inhibiting Smad2/3 and Rhoa Signaling Pathways

Hypoxia Suppresses TGF-B1-Induced Cardiac Myocyte Myofibroblast Transformation by Inhibiting Smad2/3 and Rhoa Signaling Pathways

Aspirin Reduces Cardiac Interstitial Fibrosis by Inhibiting Erk1/2-Serpine2 and P-Akt Signalling Pathways

Female Sex as a Thromboembolic Risk Factor in the Era of Nonvitamin K Antagonist Oral Anticoagulants

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