scholarly journals Cardiac Contractility Modulation Attenuate Myocardial Fibrosis by Inhibiting TGF-β1/Smad3 Signaling Pathway in a Rabbit Model of Chronic Heart Failure

2016 ◽  
Vol 39 (1) ◽  
pp. 294-302 ◽  
Author(s):  
Feifei Zhang ◽  
Yi Dang ◽  
Yingxiao Li ◽  
Qingqing Hao ◽  
Rong Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Signaling Pathway ◽  
Myocardial Fibrosis ◽  
Cardiac Contractility ◽  
Rabbit Model ◽  
Cardiac Contractility Modulation ◽  
Protein Levels ◽  
Collagen Iii ◽  
Tgf Β1

Backgroun/Aims: To explore the effect of cardiac contractility modulation (CCM) on myocardial fibrosis in heart failure and to investigate the underlying mechanism. Methods: Rabbits were randomly divided into sham group, HF group and CCM group. A rabbit model of chronic heart failure (CHF) was induced 12 weeks after aortic constriction by pressure unloading. Then cardiac contractility modulation was delivered to the myocardium lasting six hours per day for 4 weeks. Histology examination was carried out to evaluate the myocardial pathological changes. Protein levels of collagen I, collagen III, α-SMA, MMP2, MMP9, TIMP1, TGF-β1 and Smad3 were measured by western blot analysis. Results: Histology examination results showed that CCM therapy attenuated myocardial fibrosis and collagen deposition in rabbits with CHF. In addition, protein levels of collagen I, collagen III, α-SMA, MMP2, MMP9, TIMP1, TGF-β1 and Smad3 were down regulated. Conclusion: CCM therapy exerted protective effects against myocardial fibrosis potentially by inhibiting TGF-β1/Smad3 signaling pathway in CHF rabbits.

scholarly journals Cardiac contractility modulation attenuates structural and electrical remodeling in a chronic heart failure rabbit model

2020 ◽  
Vol 48 (10) ◽  
pp. 030006052096291
Author(s):  
Bin Ning ◽  
Feifei Zhang ◽  
Xuelian Song ◽  
Qingqing Hao ◽  
Yingxiao Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ventricular Tachycardia ◽  
Chronic Heart Failure ◽  
Refractory Period ◽  
Connexin 43 ◽  
Cardiac Contractility ◽  
Rabbit Model ◽  
Electrical Remodeling ◽  
Cardiac Contractility Modulation ◽  
Protein Levels

Background Cardiac contractility modulation (CCM) is non-excitatory electrical stimulation for improving cardiac function. This study aimed to evaluate the effects of CCM on structural and electrical remodeling in a rabbit model of chronic heart failure (CHF). Methods Thirty rabbits were randomly divided into the sham, CHF, and CCM groups. The CHF model was induced 12 weeks after trans-aortic constriction by pressure unloading and CCM was delivered to the myocardium for 4 weeks. Corrected QT intervals, the ventricular effective refractory period, and inducibility of ventricular tachycardia were measured by an electrophysiological examination. Connective tissue growth factor, galectin-3, Kv4.3, KCNQ1, KCNH2, and connexin 43 protein levels were measured by western blotting. Results The CHF group had a significantly prolonged corrected QT interval and ventricular effective refractory period, and increased inducibility of ventricular tachycardia. Prominent myocardial fibrosis and increased hydroxyproline content were observed in the CHF group, but these were suppressed in the CCM group. Kv4.3, KCNQ1, KCNH2, and connexin 43 protein levels were significantly lower in the CHF group, but treatment with CCM partially restored their levels. Conclusions CCM attenuates myocardial structural and electrical remodeling during CHF. These findings provide evidence for clinical use of CCM in treating CHF.

Cardiac contractility modulation regulates the structural and electrical remolding in chronic heart failure rabbit model

2019 ◽  
Author(s):  
FEIFEI ZHANG ◽  
Yi Dang ◽  
Qingqing Hao ◽  
Yingxiao Li ◽  
Rong Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ventricular Tachycardia ◽  
Chronic Heart Failure ◽  
Refractory Period ◽  
Cardiac Contractility ◽  
Rabbit Model ◽  
Effective Refractory Period ◽  
Cardiac Contractility Modulation ◽  
Failure Group ◽  
Protein Levels

Abstract Background Chronic heart failure (CHF) is accompanied by complex changes in cardiac electrophysiology and functional properties of cardiomyocytes which cause the structural and electrical remodeling process. Cardiac contractility modulation (CCM) is a novel therapeutic method and has proven to be effective in improving cardiac function. This study evaluated the effects of CCM on structural and electrical remolding in a rabbit model of CHF. Methods Thirty rabbits were randomly divided into sham group, heart failure group and CCM group. CHF model was induced 12 weeks after trans aortic constriction by pressure unloading. Then cardiac contractility modulation was delivered to the myocardium lasting six hours per day for 4 weeks. Structural changes were assessed by hydroxyproline assay and picrosirius red staining. The QTc intervals, ventricular effective refractory period and the inducibility of ventricular tachycardia were measured by electrophysiological examination. Protein levels of CTGF, Gal-3, Kv4.3, KCNQ1, KCNH2 and CX43 were measured by western blot analysis. Results Our study revealed that CHF rabbits developed significant prolonged QTc, ventricular effective refractory period and increased inducibility of ventricular tachycardia. Prominent myocardial fibrosis and increased levels of hydroxyproline content were observed in the heart failure group. Changes mentioned above can be suppressed with CCM therapy in CHF rabbits. The protein levels of CTGF, Gal-3, Kv4.3, KCNQ1, KCNH2 and CX43 significantly increased in the heart failure group, but these changes were prevented in the CCM group. Conclusions The present study demonstrated that CCM treatment prevented myocardial structural and electrical remolding in a rabbit model of CHF. The beneficial effect of CCM may be related to prevention of downregulation of the CTGF, Gal-3, Kv4.3, KCNQ1, KCNH2 and CX43. These findings provide experimental evidence for the clinical use of CCM in the treatment of HF.

scholarly journals Cardiac Contractility Modulation Attenuates Chronic Heart Failure in a Rabbit Model via the PI3K/AKT Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-8 ◽  
Author(s):  
Qingqing Hao ◽  
Feifei Zhang ◽  
Yudan Wang ◽  
Yingxiao Li ◽  
Xiaoyong Qi
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Cardiac Contractility ◽  
Rabbit Model ◽  
The Body ◽  
Heart Weight ◽  
Akt Pathway ◽  
Control Group ◽  
Cardiac Contractility Modulation ◽  
Positive Effects

The Akt plays an important role in regulating cardiac growth, myocardial angiogenesis, and cell death in cardiac myocytes. However, there are few studies to focus on the responses of the Akt pathway to cardiac contractility modulation (CCM) in a chronic heart failure (HF) model. In this study, the effects of CCM on the treatment of HF in a rabbit model were investigated. Thirty six-month-old rabbits were randomly separated into control, HF, and CCM groups. The rabbits in HF and CCM groups were pressure uploaded, which can cause an aortic constriction. Then, CCM was gradually injected to the myocardium of rabbits in the CCM group, and this process lasted for four weeks with six hours per day. Rabbit body weight, heart weight, and heart beating rates were recorded during the experiment. To assess the CCM impacts, rabbit myocardial histology was examined as well. Additionally, western blot analysis was employed to measure the protein levels of Akt, FOXO3, Beclin, Pi3k, mTOR, GSK-3β, and TORC2 in the myocardial histology of rabbits. Results showed that the body and heart weight of rabbits decreased significantly after suffering HF when compared with those in the control group. However, they gradually recovered after CCM application. The CCM significantly decreased collagen volume fraction in myocardial histology of HF rabbits, indicating that CCM therapy attenuated myocardial fibrosis and collagen deposition. The levels of Akt, FOXO3, Beclin, mTOR, GSK-3β, and TORC2 were significantly downregulated, but Pi3k concentration was greatly upregulated after CCM utilization. Based on these findings, it was concluded that CCM could elicit positive effects on HF therapy, which was potentially due to the variation in the Pi3k/Akt signaling pathway.

scholarly journals MiRNA-1202 promotes the TGF-β1-induced proliferation, differentiation and collagen production of cardiac fibroblasts by targeting nNOS

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0256066
Author(s):  
Jingwen Xiao ◽  
Yan Zhang ◽  
Yuan Tang ◽  
Hengfen Dai ◽  
Yu OuYang ◽  
...  
Keyword(s):  
Protein Expression ◽  
Myocardial Fibrosis ◽  
Cardiac Fibroblasts ◽  
Collagen I ◽  
Luciferase Reporter ◽  
Control Group ◽  
Protein Levels ◽  
Collagen Iii ◽  
Human Cardiac Fibroblasts ◽  
Tgf Β1

Background Atrial fibrillation (AF) is a clinically common arrhythmia that affects human health. Myocardial fibrosis serves as an important contributor to AF. Recently, miRNA-1202 have been reported to be up-regulated in AF. However, the role of miRNA-1202 and its mechanism in myocardial fibrosis remain unclear. Methods Human cardiac fibroblasts (HCFs) were used to construct a fibrosis model by TGF-β1 induction. The expression of miR-1202 was measured by qRT-PCR. Cell proliferation was assessed by CCK-8 assays. Protein expression levels were measured by western blot. Collagen accumulation was measured by ELISA. The relationship between miR-1202 and nNOS was investigated by luciferase reporter assays. Results MiR-1202 expression was obviously increased in HCFs and was both time- and dose-independent. MiR-1202 could increase the proliferation and collagen I, collagen III, and α-SMA levels with or without TGF-β1. MiR-1202 could also increase TGF-β1 and p-Smad2/3 protein levels in comparison to the control group. However, they were obviously decreased after inhibitor transfection. MiR-1202 targets nNOS for negative regulation of HCFs fibrosis by decreasing cell differentiation, collagen deposition and the activity of the TGF-β1/Smad2/3 pathway. Co-transfection of miR-1202 inhibitor and siRNA of nNOS inhibited nNOS protein expression, thereby enhancing the HCFs proliferation. Furthermore, co-transfection of the miR-1202 inhibitor and siRNA of nNOS significantly promoted collagen I, collagen III, TGF-β1, Smad2/3 and α-SMA protein expression and Smad2/3 protein phosphorylation. These findings suggested that miR-1202 promotes HCFs transformation to a pro-fibrotic phenotype by targeting nNOS through activating the TGF-β1/Smad2/3 pathway.

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