Simvastatin alleviates cardiac fibrosis induced by infarction via up‐regulation of TGF ‐β receptor III expression
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Abstract:
Statins decrease heart disease risk, but their mechanisms are not completely understood. We examined the role of the TGF-β receptor III (TGFBR3) in the inhibition of cardiac fibrosis by simvastatin.Myocardial infarction (MI) was induced by ligation of the left anterior descending coronary artery in mice given simvastatin orally for 7 days. Cardiac fibrosis was measured by Masson staining and electron microscopy. Heart function was evaluated by echocardiography. Signalling through TGFBR3, ERK1/2, JNK and p38 pathways was measured using Western blotting. Collagen content and cell viability were measured in cultures of neonatal mouse cardiac fibroblasts (NMCFs). Interactions between TGFBR3 and the scaffolding protein, GAIP-interacting protein C-terminus (GIPC) were detected using co-immunoprecipitation (co-IP). In vivo, hearts were injected with lentivirus carrying shRNA for TGFBR3.Simvastatin prevented fibrosis following MI, improved heart ultrastructure and function, up-regulated TGFBR3 and decreased ERK1/2 and JNK phosphorylation. Simvastatin up-regulated TGFBR3 in NMCFs, whereas silencing TGFBR3 reversed inhibitory effects of simvastatin on cell proliferation and collagen production. Simvastatin inhibited ERK1/2 and JNK signalling while silencing TGFBR3 opposed this effect. Co-IP demonstrated TGFBR3 binding to GIPC. Overexpressing TGFBR3 inhibited ERK1/2 and JNK signalling which was abolished by knock-down of GIPC. In vivo, suppression of cardiac TGFBR3 abolished anti-fibrotic effects, improvement of cardiac function and changes in related proteins after simvastatin.TGFBR3 mediated the decreased cardiac fibrosis, collagen deposition and fibroblast activity, induced by simvastatin, following MI. These effects involved GIPC inhibition of the ERK1/2/JNK pathway.Keywords:
Cardiac Fibrosis
Myocardial fibrosis
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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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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Myocardial fibrosis is the common pathological basis of several cardiac diseases.It is now well known that transforming growth factor-β1 and hepotocyte growth factor respectively promote and inhibit myocardial fibrosis,their mutual downstream-connective tissue growth factor,is important for mediation of positive and negative regulation in myocardial fibrosis,thus it shows new ways to treat cardiac diseases. Some recent advancements of this area reviewed in this article.
Myocardial fibrosis
Cardiac Fibrosis
Endomyocardial fibrosis
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Objective To observe the effect of astragalus membranaous on UrotensinⅡ(UⅡ)-induced collagen synthesis and transforming growth factor-β1 scretion of cardiac fibroblasts.Methods The neonatal cardiac fibroblasts were cultured and the forth generation cells were allocated into 3 groups:control group (cells were cultured under normal conditions),UⅡ groups(cells were cultured with 10～7mol/L UⅡ),astragalus membranaous groups(cells were cultured with 10～7mol/L UⅡ and 40mg/L astragalus membranaous)respectively.After certain periods of time,the mRNA expression of collagenⅠ,collagen Ⅲ and TGF-β1 were measured by real-time RT-PCR,collagen synthesis was measured by 3H-proline incorporation and TGF-β1 secretion was measured by ELISA.Results UⅡ significantly induced collagen synthesis and secretion of TGF-β1 in neonatal cardiac fibroblasts in vitro and astragalus membranous could reduce these effects of UⅡ.Conclusion Astragalus membranaous can delay the progression of cardiac fibrosis and cardiac remodeling by inhibiting the UⅡ-induced collagen synthesis and TGF-β1 secretion in cardiac fibroblasts.
Cardiac Fibrosis
Astragalus
Urotensin II
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AIM: To investigate the effects of simvastatin on myocardial fibrosis in NO deficient hypertensive rats. METHODS: Twenty four male Wistar Kyoto rats were divided into three groups: Control (C) group, L NAME (L) group, and L NAME plus Simvastatin (L+S) group. The levels of ACE and AngⅡ in plasma and myocardial tissue, and the contents of hydroxyproline concentration in myocardial tissue were measured after 8 weeks. The values of CVF, PVCA and the hydroproline concentration (HC) were studied using the methods of pathological examination combined with computed processing. RESULTS: The activity of ACE in serum in L group was lower than that in C group (P 0.01 ). Simvastatin treatment did not significantly increase the activity of ACE compared with L group (P 0.05 ). However, the activity of ACE in myocardial tissue was lower than that of C group (P 0.05 ). Although the levels of AngⅡ in plasma were not altered by L NAME (P 0.05 ), the concentrations of AngⅡ in myocardial tissue (P 0.01 ) were significantly increased in L group compared to C group. Simvastatin significantly decreased the levels of AngⅡ in myocardial tissue (P 0.05 ). The hydroxyproline concentration and the value of PVCA and CVF in L group were significantly higher than that in C group (P 0.01 ), which were significantly attenuated by simvastatin tratment (P 0.05 ). CONCLUSION: Simvastatin may decrease the production of AngⅡ and attenuate myocardial fibrosis via reducing the activity of ACE in NO deficient hypertensive rats.
Hydroxyproline
Myocardial fibrosis
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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
Myocardial fibrosis
Cardiac Fibrosis
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Objective To investigate the effect of simvastatin treatment of diabetic patients with coronary artery disease lipid and cardiac function. Methods Using a random number table 120 cases of diabetic patients with coronary artery disease were divided into two groups and the control group(60 cases) and control group was treated with conventional treatment, observation group were treated with simvastatin were based on the observation of three lipid levels in patients before and after treatment and cardiac function parameters change. Results After treatment, the two groups of patients with TG,TC, LDL-C levels were significantly lower than before treatment significantly increased HDL-C compared with before treatment, there was a significant difference(P0.05) and between groups; observation group after treatment LVEF, 6MHW significantly higher, LVESD, LVEDD were significantly lower than the control group(P 0.05). Treatment observation group total effective rate was significantly higher(P0.05).Adverse reactions of observed group was 6.67%, the control group was 5.00%,there was no significant difference(P0.05) between the two groups. Conclusion Simvastatin treatment of diabetes and coronary heart disease, which can effectively reduce blood lipid levels, while improving cardiac function in patients, significant clinical effect has important applications.
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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
Myocardial fibrosis
Apelin
Pressure overload
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