Upregulation of miR-128 Mediates Heart Injury by Activating Wnt/β-catenin Signaling Pathway in Heart Failure Mice

AbstractIn heart failure (HF) caused by hypertension, the myocyte size increases, and the cardiac wall thickens. A low-molecular-weight compound called ICG001 impedes β-catenin-mediated gene transcription, thereby protecting both the heart and kidney. However, the HF-preventive mechanisms of ICG001 remain unclear. Hence, we investigated how ICG001 can prevent cardiac hypertrophy and fibrosis induced by transverse aortic constriction (TAC). Four weeks after TAC, ICG001 attenuated cardiac hypertrophy and fibrosis in the left ventricular wall. The TAC mice treated with ICG001 showed a decrease in the following: mRNA expression of brain natriuretic peptide (Bnp), Klf5, fibronectin, β-MHC, and β-catenin, number of cells expressing the macrophage marker CD68 shown in immunohistochemistry, and macrophage accumulation shown in flow cytometry. Moreover, ICG001 may mediate the substrates in the glycolysis pathway and the distinct alteration of oxidative stress during cardiac hypertrophy and HF. In conclusion, ICG001 is a potential drug that may prevent cardiac hypertrophy and fibrosis by regulating KLF5, immune activation, and the Wnt/β-catenin signaling pathway and inhibiting the inflammatory response involving macrophages.

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Silencing circ_0062389 alleviates cardiomyocyte apoptosis in heart failure rats via modulating TGF-β1/Smad3 signaling pathway

Gene ◽

10.1016/j.gene.2020.145154 ◽

2021 ◽

Vol 766 ◽

pp. 145154

Author(s):

Yongjun Zhang ◽

Bin Chen

Keyword(s):

Heart Failure ◽

Signaling Pathway ◽

Cardiomyocyte Apoptosis ◽

Tgf Β1

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WNT3A rs752107(C > T) Polymorphism Is Associated With an Increased Risk of Essential Hypertension and Related Cardiovascular Diseases

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.675222 ◽

2021 ◽

Vol 8 ◽

Author(s):

Huan Ren ◽

Jian-Quan Luo ◽

Fan Ouyang ◽

Li Cheng ◽

Xiao-Ping Chen ◽

...

Keyword(s):

Heart Failure ◽

Essential Hypertension ◽

Signaling Pathway ◽

Genetic Variant ◽

Eqtl Analysis ◽

Cardiovascular Development ◽

Genomic Variants ◽

Increased Risk ◽

First Time

Essential Hypertension (EH) results in the burden of cardiovascular disease (CVD) such as Heart Failure (HF) and Ischemic Stroke (IS). A rapidly emerging field involving the role of Wnt/β-catenin signaling pathway in cardiovascular development and dysfunction has recently drawn extensive attention. In the present study, we conducted a genetic association between genomic variants in Wnt/β-catenin signaling pathway and EH, HF, IS. A total of 95 SNPs in 12 Wnt signaling genes (WNT3A, WNT3, WNT4, DKK1, DKK2, LRP5, LRP6, CTNNB1, APC, FZD1, FRZB, SFRP1) were genotyped in 1,860 participants (440 patients with EH, 535 patients with HF, 421 patients with IS and 464 normal control subjects) using Sequenom MassArray technology. WNT3A rs752107(C > T) was strongly associated with an increased risk of EH, HF and IS. Compared with WNT3A rs752107 CC genotype, the CT genotype carriers had a 48% increased risk of EH (OR = 1.48, 95% CI = 1.12–1.96, P = 0.006), the TT genotype conferred a 139% increased risk of EH (OR = 2.39, 95% CI = 1.32–4.34, P = 0.003). Regarding HF and IS, the risk of HF in the T allele carriers (CT + TT) was nearly increased by 58% (OR = 1.58, 95% CI = 1.22–2.04, P = 4.40 × 10−4) and the risk of IS was increased by 37% (OR = 1.37, 95% CI = 1.04–1.79, P = 0.025). Expression quantitative trait loci (eQTL) analysis indicated that rs752107 C allele corresponded to a significant reduction of WNT3A expression. We described a genetic variant of WNT3A rs752107 in Wnt/β-catenin signaling strongly associated with the risk of EH, HF and IS for the first time.

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Effect of miR-195-5p on cardiomyocyte apoptosis in rats with heart failure by regulating TGF-β1/Smad3 signaling pathway

Bioscience Reports ◽

10.1042/bsr20200566 ◽

2020 ◽

Vol 40 (5) ◽

Author(s):

Chun Xie ◽

Huaxin Qi ◽

Lei Huan ◽

Yan Yang

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Signaling Pathway ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β1 ◽

Cardiomyocyte Apoptosis ◽

Luciferase Reporter ◽

Rat Cardiomyocytes ◽

Smad 3 ◽

Tgf Β1

Abstract Purpose: The present study set out to investigate the effect of miR-195-5p on cardiomyocyte apoptosis in rats with heart failure (HF) and its mechanism. Methods: HF rat model and hypoxia/reoxygenation (H/R) cardiomyocyte model were established. miR-195-5p expression and transforming growth factor-β1 (TGF-β1)/signal transduction protein (Smad)3 signaling pathway in HF rats and H/R cardiomyocytes were interfered. miR-195-5p expression was tested by Rt-PCR, TGF-β1/Smad3 signaling pathway related proteins were detected by Western Blot, apoptosis of HF rat cardiomyocytes was tested by TUNEL, and apoptosis of cardiomyocytes induced by H/R was checked by flow cytometry. Results: miR-195-5p was lowly expressed in myocardium of HF rats, while TGF-β1 and Smad3 proteins were high-expressed. Up-regulating miR-195-5p expression could obviously inhibit cardiomyocyte apoptosis of HF rats, improve their cardiac function, and inhibit activation of TGF-β1/Smad3 signaling pathway. Up-regulation of miR-195-5p expression or inhibition of TGF-β1/Smad3 signaling pathway could obviously inhibit H/R-induced cardiomyocyte apoptosis. Dual-luciferase reporter enzyme verified the targeted relationship between miR-195-5p and Smad3. Conclusion: miR-195-5p can inhibit cardiomyocyte apoptosis and improve cardiac function in HF rats by regulating TGF-β1/Smad3 signaling pathway, which may be a potential target for HF therapy.

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Pravastatin slows the progression of heart failure by inhibiting the c-Jun N-terminal kinase-mediated intrinsic apoptotic signaling pathway

Molecular Medicine Reports ◽

10.3892/mmr.2013.1622 ◽

2013 ◽

Vol 8 (4) ◽

pp. 1163-1168 ◽

Cited By ~ 9

Author(s):

SHIPING CAO ◽

ZHI ZENG ◽

XIANBAO WANG ◽

JIANPING BIN ◽

DINGLI XU ◽

...

Keyword(s):

Heart Failure ◽

Signaling Pathway ◽

Apoptotic Signaling

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Identification of transcription factors MYC and C/EBPβ mediated regulatory networks in heart failure based on GEO dataset

10.21203/rs.2.16967/v2 ◽

2020 ◽

Author(s):

Haiwei Wang ◽

Xinrui Wang ◽

Liangpu Xu ◽

Hua Cao

Keyword(s):

Heart Failure ◽

Transcription Factors ◽

Signaling Pathways ◽

Signaling Pathway ◽

Insulin Signaling ◽

Regulatory Networks ◽

Target Genes ◽

Transcriptional Profiling ◽

Insulin Signaling Pathway ◽

Failing Heart

Abstract Background: Heart failure is one of leading cause of death worldwide. However, the transcriptional profiling of heart failure is unclear. Moreover, the signaling pathways and transcription factors involving the heart failure development also are largely unknown. Using published Gene Expression Omnibus (GEO) datasets, in the present study, we aim to comprehensively analyze the differentially expressed genes in failing heart tissues, and identified the critical signaling pathways and transcription factors involving heart failure development. Methods: The transcriptional profiling of heart failure was identified from previously published gene expression datasets deposited in GSE5406, GSE16499 and GSE68316. The enriched signaling pathways and transcription factors were analyzed using DAVID website and gene set enrichment analysis (GSEA) assay. The transcriptional networks were created by Cytoscape. Results: Compared with the normal heart tissues, 90 genes were particularly differentially expressed in failing heart tissues, and those genes were associated with multiple metabolism signaling pathways and insulin signaling pathway. Metabolism and insulin signaling pathway were both inactivated in failing heart tissues. Transcription factors MYC and C/EBPβ were both negatively associated with the expression profiling of failing heart tissues in GSEA assay. Moreover, compared with normal heart tissues, MYC and C/EBPβ were down regulated in failing heart tissues. Furthermore, MYC and C/EBPβ mediated downstream target genes were also decreased in failing heart tissues. MYC and C/EBPβ were positively correlated with each other. At last, we constructed MYC and C/EBPβ mediated regulatory networks in failing heart tissues, and identified the MYC and C/EBPβ target genes which had been reported involving the heart failure developmental progress. Conclusions: Our results suggested that metabolism pathways and insulin signaling pathway, transcription factors MYC and C/EBPβ played critical roles in heart failure developmental progress.

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Effect of Shenfu Qiangxin on the expression of TGF-β/Smads signaling pathway-related molecules in myocardium of rats with heart failure

European Journal of Inflammation ◽

10.1177/2058739219852854 ◽

2019 ◽

Vol 17 ◽

pp. 205873921985285

Author(s):

Li Xiong ◽

Guobo Xie ◽

Binhua Luo ◽

Zhiliang Mei

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Signaling Pathway ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Tgf Beta ◽

Model Group ◽

Ventricular Ejection Fraction ◽

Tnf Α ◽

Losartan Group

This study aims to evaluate the effect of Shenfu Qiangxin on TGF-β/Smads signaling pathway-related molecules in myocardial tissue of rats with heart failure. Five rats were selected as sham-operated group, while another 15 rats with heart failure were divided into three groups, including model group, losartan group, and Shenfu Qiangxin group. Rats in losartan group were given losartan intragastric intervention, the rats in Shenfu Qiangxin group were given Shenfu Qiangxin mixture intervention, while rats in another two groups were given equal volume of sterile saline intervention. During the treatment, the levels of B-type brain natriuretic peptide (BNP), lactate dehydrogenase (LDH), free fatty acids (FFA), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and TGF-β/Smads signaling pathway were measured in rats. Compared with model group, the expression of ejection fraction (EF), left ventricular ejection fraction (LVSP), TGF-β 1, Smad2, and Smad3 significantly decreased in sham-operated group, losartan group, and Shenfu Qiangxin group, while left ventricular end-diastolic volume (LVEDV), left ventricular end-diastolic diameter (LVDd), left ventricular end-diastolic pressure (LVEDP), BNP, LDH, FFA, TNF-α, and IL-6 levels increased ( P < 0.05). Compared with sham-operated group, the expression of EF, LVSP, TGF-beta 1, Smad2, and Smad3 dramatically decreased in losartan group, Shenfu Qiangxin group, but LVEDV, LVDd, LVEDP, BNP, LDH, FFA, TNF-α, and IL-6 levels increased ( P < 0.05). Compared with losartan group, the expression of EF, LVSP, TGF-beta 1, Smad2, and Smad3 upregulated in Shenfu Qiangxin group, while LVEDV, LVDd, LVEDP, BNP, LDH, FFA, TNF-α, and IL-6 levels downregulated ( P < 0.05). Consequently, Shenfu Qiangxin could effectively improve the heart function of rats with heart failure, and play an anti-heart failure role by regulating the expression of related molecules of TGF-β/Smads signaling pathway.

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