Suppression of miR-143-3p contributes to the anti-fibrosis effect of atorvastatin on myocardial tissues via the modulation of Smad2 activity
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Myocardial fibrosis
Cardiac Fibrosis
In May 2012, generic atorvastatin has become available in Belgium. This study examines the impact of market entry of generic atorvastatin on Belgian statin market and on cost-effectiveness of statin therapy. Using IMS Health data, the Belgian 2000-2011 statin market was analyzed in terms of total expenditure, annual price of statin treatment, and number of patients. Also, a simulation analysis projected market shares in the Belgian statin market from 2012 to 2015 following market entry of generic atorvastatin. This analysis was based on three scenarios regarding the number of patients taking specific statins. Savings associated with an atorvastatin price reduction of 50%-70% were calculated. A literature review of economic evaluations was conducted to assess the cost-effectiveness of generic atorvastatin. Statin expenditure more than doubled from €113 million in 2000 to €285 million in 2011, mainly as a result of higher expenditure on atorvastatin and rosuvastatin. Although the number of patients treated with simvastatin increased by nearly 800% during 2000-2011, the resulting increase in expenditure was partially offset by price reductions due to generic competition and a simvastatin tender. The simulation analysis indicated that atorvastatin will become the dominant product in the Belgian statin market (market share by expenditure of 47%-66% by 2015). Annual savings were projected to attain €108.6-€153.7 million for a 50% reduction in the atorvastatin price and €152.0-€215.2 million for a 70% price reduction. The literature suggests that generic atorvastatin is cost-effective as compared to simvastatin and becomes more cost-effective at higher daily doses. The limited evidence about the cost-effectiveness of rosuvastatin as compared with generic atorvastatin is inconclusive. Generic atorvastatin is cost-effective as compared to simvastatin, is projected to become the dominant product in the Belgian statin market and is expected to generate substantial savings to health care payers.
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Cardiac fibrosis is a primary event during myocardial infarction (MI) progression, which impairs cardiac function. The present study aimed to investigate the effect of SGLT2 on cardiac fibrosis following MI. To validate the role of SGLT2 in the regulation of cardiac fibrosis in vivo, an MI rat model was established. Echocardiography was performed to determine cardiac function at 4 weeks post‑MI. MI model rats were transfected with short hairpin RNA (sh)‑SGLT2 or sh‑negative control lentiviruses to investigate the effect of SGLT2 on rat heart function post‑MI. Subsequently, the effects of SGLT2 on the cardiac fibrosis of infarcted hearts were assessed by performing Masson's trichrome staining. To further clarify the effect of SGLT2 on cardiac fibroblast proliferation, TGFβ was used to stimulate primary cardiac fibroblasts in vitro. The results demonstrated that SGLT2 served a key role in cardiac fibrosis. SGLT2 expression levels in infarct tissues were significantly increased at week 1 post‑MI compared with the sham group. Compared with the control group, SGLT2 knockdown attenuated cardiac fibrosis by inhibiting the expression of collagen I and collagen III in cardiac fibroblasts in vitro and in vivo. Furthermore, the results indicated that SGLT2 expression was modulated by miR‑141 in cardiac fibroblasts. In summary, the present study indicated that upregulated SGLT2 expression in cardiac fibrosis following MI was regulated by miR‑141 and SGLT2 that knockdown reduced cardiac fibrosis and improved cardiac function after MI.
Cardiac Fibrosis
Myocardial fibrosis
Masson's trichrome stain
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Abstract Background: Endothelial-to-mesenchymal transition (Endo-MT) is associated with myocardial fibrosis in dilated cardiomyopathy (DCM). Endothelial-to-mesenchymal transition (Endo-MT) is induced by coxsackievirus B3 (CVB3) in cardiac microvascular endothelial cells (CMVECs). Bone morphogenetic protein 7 (BMP7) significantly inhibits Endo-MT and the progression of cardiac fibrosis. The study was aimed to investigate the effect and the underlying mechanism of BMP7 on Endo-MT in myocardial fibrosis induce by CVB3 infection in vivo. Methods: BALB/c mice were intraperitoneally injected by CVB3 to induce viral myocarditis (VMC). Mice were treated with BMP7 after CVB3 infection. Subsequently, all groups of mice were determined by echocardiography, histopathologic and molecular detection. Results: We found that the ratio of BMP7/TGF-β1 in mRNA levels was decreased obviously at different time points after CVB3 injection. BMP7 facilitated the recovery of cardiac function after CVB3 infection via inhibition of myocardial damage, collagen deposition. Double immunofluorescence staining indicated that Endo-MT was implicated in CVB3-induced myocardial fibrosis, which was attenuated by BMP7. The protein levels of pSmad3 and Smad4 were significantly upregulated in VMC group, as well as Wnt/β-catenin and the transcription factor snail. BMP7 treatment reversed the changes of these protein levels. Moreover, CO-IP demonstrated the crosstalk between β-catenin and Smad3 in VMC mice, which was downregulated by BMP7 treatment. Conclusions: These results indicated that BMP7 obviously ameliorated myocardial fibrosis in CVB3-infected mice via Endo-MT, which was involved in the TGF-β/Smad and Wnt/β-catenin pathway. β-Catenin/Smad3 interaction may be associated with Endo-MT in the development of viral myocardial fibrosis.
Myocardial fibrosis
Cardiac Fibrosis
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Cardiac Fibrosis
Myocardial fibrosis
Pathophysiology
Senescence
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Background: Although few microRNAs (miRNAs) have been involved in the regulation of post-ischemic cardiac fibrosis, the exact effect and underlying mechanism of miRNAs in cardiac fibrosis remains unclear. Here, we sought to investigate whether microRNA-34 (miR-34) plays a role in the pathogenic development of myocardial fibrosis.Methods: The myocardial infarction (MI) mice model was induced and cardiac fibroblasts were cultured. Histological analyses, quantitative real-time polymerase chain reaction and Western blotting analysis were used.Results: We found that the miR-34 cluster, especially miR-34a, was upregulated in the MI heart. In vivo, inhibition of miR-34a reduces the severity of experimental cardiac fibrosis in mice. TGF-β1 increased miR-34a expression in cardiac fibroblasts. Overexpressing miR-34a levels increased the profibrogenic activity of TGF-β1 in cardiac fibroblast, whereas inhibition miR-34a levels weakened the activity. Finally, we showed that miR-34a's underlying mechanism during cardiac fibrosis occurs through the targeting of Smad4 expression.Conclusions: Our findings provide evidence that miR-34a plays a critical role in the progression of cardiac tissue fibrosis by directly targeting Smad4, which suggests that miR-34a may be new marker for cardiac fibrosis progression and that inhibition of miR-34a may be a promising strategy in the treatment of cardiac fibrosis.
Cardiac Fibrosis
Myocardial fibrosis
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Myocardial fibrosis
Cardiac Fibrosis
Masson's trichrome stain
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Objective To investigate the influence and the mechanisms involved in the regression of apocynum venetum extract(AVE)on Ang Ⅱ-induced myocardial fibrosis.AVE on myocardial fibrosis.Methods Rat cardiac fibroblasts were pretreated with Ang Ⅱ,and then,treated with different concentrations of AVE(0.8mol·L-1、0.4mol·L-1、0.2mol·L-1).The effect of AVE on the proliferation of cardiac fibroblast stimulated by Ang Ⅱ was detected by MTT,while the expression of Col Ⅰ/Col Ⅲ and TGF-β by ELISA and RT-PCR.Results In the cardiac fibroblast,the over expression of Col Ⅰ and Col Ⅲ,induced by Ang II,could be inhibited by AVE.What's more,compared with C group,TGF-β was increased obviously in the Ang Ⅱ group,and all the AVE groups were able to inhibit the increament of TGF-β stimulated by AngII.Conclusion AVE can reduce the expression of mRNA and protein of TGF-β,and as a result,lighten myocardial fibrosis
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Cardiac Fibrosis
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In 2011, Manitoba implemented a province-wide program of physician detailing and free sampling for generic atorvastatin to increase use of this generic statin. We examined the impact of this unique combined program of detailing and sampling for generic atorvastatin on the use and cost of statin medicines, market share of generic atorvastatin, the choice of starting statin for new users, and switching from a branded statin to generic atorvastatin.We conducted a retrospective study of Manitoba insurance claims data for all continuously enrolled patients who filled one or more prescriptions for a statin between 2008 and 2013. Data were linked to physician-level data on the number of detailing visits and sample provision. We used interrupted time series analyses to assess policy-related changes in the use and cost of statin medicines, market share of generic atorvastatin, the choice of starting statin for new users, and switching from a branded statin to generic atorvastatin.The detailing program reached 31% (651/2103) of physicians who prescribed a statin during the study period. Collectively, these physicians prescribed 61% of statins dispensed in the province. Free sample cards were provided to 61% (394/651) of the detailed physicians. The program did not change the level or trend in the overall statin use rate and the total cost of statins or increase the number of patients switching from another branded statin to generic atorvastatin. We found the program had a small impact on atorvastatin's market share of new prescriptions, with a level increase of 2.6%.Though physician detailers were skilled at targeting high-prescribing physicians, a combined program of detailing visits and sample provision for generic atorvastatin did not lower overall statin costs or lead to switching from branded statins to the generic. The preceding introduction of generic atorvastatin appeared sufficient to modify prescribing patterns and decrease costs.
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Cardiac fibrosis stiffens the ventricular wall, predisposes to cardiac arrhythmias and contributes to the development of heart failure. In the present study, our aim was to identify novel miRNAs that regulate the development of cardiac fibrosis and could serve as potential therapeutic targets for myocardial fibrosis.Analysis for cardiac samples from sudden cardiac death victims with extensive myocardial fibrosis as the primary cause of death identified dysregulation of miR-185-5p. Analysis of resident cardiac cells from mice subjected to experimental cardiac fibrosis model showed induction of miR-185-5p expression specifically in cardiac fibroblasts. In vitro, augmenting miR-185-5p induced collagen production and profibrotic activation in cardiac fibroblasts, whereas inhibition of miR-185-5p attenuated collagen production. In vivo, targeting miR-185-5p in mice abolished pressure overload induced cardiac interstitial fibrosis. Mechanistically, miR-185-5p targets apelin receptor and inhibits the anti-fibrotic effects of apelin. Finally, analysis of left ventricular tissue from patients with severe cardiomyopathy showed an increase in miR-185-5p expression together with pro-fibrotic TGF-β1 and collagen I.Our data show that miR-185-5p targets apelin receptor and promotes myocardial fibrosis.
Cardiac Fibrosis
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Pressure overload
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