scholarly journals Naringenin Protects Rats against Ang-II Induced Cardiac Hypertrophy and Fibrosis by Downregulating TGF-β1/Smads Signaling Pathways

2021 ◽  
Author(s):  
Xiaowei Chen ◽  
Xi Zhao ◽  
Han Wang ◽  
Hengdao Liu
Keyword(s):  
Signaling Pathway ◽  
Cardiac Remodeling ◽  
Cardiac Fibroblasts ◽  
Biological Properties ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
In Vitro Experiments ◽  
Sprague Dawley ◽  
Tgf Β1

Abstract Background:Naringenin (Nrg), a flavone found in several plant foods with various biological properties, has been shown prevention of cardiac remodeling. However, themechanisms underlying this suppression of cardiac remodeling has not been known clearly.Methods: Male Sprague Dawley (SD) rats were AngII infused via osmotic minipumps for 4 weeks and were given Nrg by gavage (100mg/kg/day) at the same time. In vitro experiments used cardiomyocyte and cardiac fibroblasts(CF) treated with AngII or AngII plus Nrg.Cardiac remodeling was assessed using the echocardiography and histological analysis. And, the effect of Nrg on TGF-β1/Smadssignaling pathway was investigated.Results: Treatmentwith Nrg(100mg/kg/day) decreased the ratio of heart weight to tibia length and hypertrophy markers in rats given AngII infusion. In vitro experiments demonstrated that AngII-induced cardiomyocyte hypertrophy and proliferation of CFs were significantly inhibited by Nrg administration. Nrg inhibited activation of the TGF-β1/Smad2/3 signaling pathway stimulated by AngII. Conclusions: Nrgsupplementation prevented cardiac remodeling via down-regulating the TGF-β1/Smad2/3 signaling pathway both in cardiomyocyte and CFs, and attenuating cardiac remodeling in AngII-induced rats model.

scholarly journals Asiatic acid alleviates Ang-II induced cardiac hypertrophy and fibrosis via miR-126/PIK3R2 signaling

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Haiyu Li ◽  
Xiaoxu Tian ◽  
Yongjuan Ruan ◽  
Junhui Xing ◽  
Zhe Meng
Keyword(s):  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Cardiac Fibroblasts ◽  
Akt Signaling ◽  
Pathological Process ◽  
Heart Weight ◽  
Asiatic Acid ◽  
Akt Signaling Pathway ◽  
Sprague Dawley

Abstract Background Cardiac hypertrophy is an independent risk factor of many cardiovascular diseases. Studies have demonstrated that microRNA-126 (miR-126) was involved in angiogenesis during physiological and pathological process. However, its role in cardiac hypertrophy has not been known clearly. Our previous study demonstrated that asiatic acid (AA) has obvious protective effect on cardiac hypertrophy. Here, this study aimed to discover the regulatory role of miR-126 and its mechanism in cardiac hypertrophy, and to determine whether AA’s anti-hypertrophy effect is partially miR-126 dependent. Methods Male Sprague Dawley rats were AngII infused via osmotic minipumps for 4 weeks and were treated with AA (20 mg/kg/day) by oral gavage. Cardiac hypertrophy was assessed using the echocardiography and histological analysis. In vitro studies,cardiomyocyte and cardiac fibroblasts (CF) were treted with AngII and AngII plus AA. And, the effect of AA on miR-126 and PI3K/AKT signaling pathway was investigated. Results Treatment of rats with AA decreased the ratio of heart weight to tibia length and hypertrophy markers. In vitro exprements demonstrated that AA significantly attenuated AngII-induced cardiac growth and cardiac fibroblast collagen expression. Moreover, our results found downregulation of miR-126 and activation of PI3K/AKT signaling pathway in AngII infusion induced cardiac hypertrophy model. It was also determined that miR-126 targets PIK3R2 directly. Conclusions AA supplementation upregulated the expression of miR-126 and conferred cardio-protection effect against AngII induced cardiac hypertrophy.

scholarly journals Zi Shen Huo Luo Formula Prevents Aldosterone-Induced Cardiomyocyte Hypertrophy and Cardiac Fibroblast Proliferation by Regulating the Striatin-Mediated MR/EGFR/ERK Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Weike Feng ◽  
Yue Zhao ◽  
Xiaotong Song ◽  
Yuan Wang ◽  
Qian Chen ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Cardiac Fibroblasts ◽  
Animal Experiments ◽  
Left Ventricular ◽  
Erk Signaling ◽  
Cardiomyocyte Hypertrophy ◽  
Membrane Localization ◽  
Myocardial Remodeling ◽  
Rat Cardiomyocytes

Inappropriate activation of the renin-angiotensin-aldosterone system (RAAS) is an important factor in the development of hypertension. Excessive aldosterone can lead to myocardial extracellular matrix collagen proliferation, fibrosis, and cardiomyocyte hypertrophy and aggravate maladaptive remodeling. The results of our previous clinical and animal experiments suggested that Zi Shen Huo Luo Formula (ZSHLF) combined with perindopril can effectively control the process of left ventricular hypertrophy (LVH). The purpose of this study was to investigate whether ZSHLF-treated serum inhibits the membrane localization of the striatin-mediated mineralocorticoid receptor (MR) and affects MR-mediated nongenomic effects and the downstream epidermal growth factor receptor (EGFR)/extracellular regulated kinase (ERK) signaling pathways, thereby improving aldosterone-induced myocardial remodeling. Serum containing ZSHLF was prepared and used to treat rat cardiomyocytes and cardiac fibroblasts in vitro after aldosterone induction and striatin knockdown by small interfering RNA (siRNA). Cell-based assays were carried out to determine the cardiomyocyte surface area and assess the proliferation rate and hydroxyproline secretion of cardiac fibroblasts. Quantitative real-time PCR (qRT-PCR), immunoprecipitation (IP), and Western blotting were performed to evaluate the striatin-mediated MR/EGFR/ERK signaling pathway. In the present study, ZSHLF attenuated the aldosterone-induced hypertrophy of cardiomyocytes and inhibited the proliferation and collagen synthesis of cardiac fibroblasts. ZSHLF also reduced striatin mRNA expression and inhibited striatin and MR binding, membrane MR protein expression, and EGFR and ERK1/2 phosphorylation. Furthermore, after striatin silencing with siRNA, some of the effects of ZSHLF were not changed significantly. In conclusion, ZSHLF inhibits the downstream EGFR/ERK signaling pathway by blocking the striatin-mediated membrane localization of MR, which may be an important molecular mechanism by which ZSHLF improves aldosterone-induced myocardial remodeling.

scholarly journals Magnolol Attenuates Right Ventricular Hypertrophy and Fibrosis in Hypoxia-Induced Pulmonary Arterial Hypertensive Rats Through Inhibition of the JAK2/STAT3 Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Minyi Fu ◽  
Fangmei Luo ◽  
Eli Wang ◽  
Yueping Jiang ◽  
Shao Liu ◽  
...  
Keyword(s):  
Right Ventricular ◽  
Signaling Pathway ◽  
Cardiac Fibroblasts ◽  
Sprague Dawley ◽  
Clinical Value ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Pulmonary Arterial

Right ventricular (RV) remodeling is one of the essential pathological features in pulmonary arterial hypertension (PAH). RV hypertrophy or fibrosis are the leading causes of RV remodeling. Magnolol (6, 6′, 7, 12-tetramethoxy-2,2′-dimethyl-1-β-berbaman, C18H18O2) is a compound isolated from Magnolia Officinalis. It possesses multiple pharmacological activities, such as anti-oxidation and anti-inflammation. This study aims to evaluate the effects and underlying mechanisms of magnolol on RV remodeling in hypoxia-induced PAH. In vivo, male Sprague Dawley rats were exposed to 10% O2 for 4 weeks to establish an RV remodeling model, which showed hypertrophic and fibrotic features (increases of Fulton index, cellular size, hypertrophic and fibrotic marker expression), accompanied by an elevation in phosphorylation levels of JAK2 and STAT3; these changes were attenuated by treating with magnolol. In vitro, the cultured H9c2 cells or cardiac fibroblasts were exposed to 3% O2 for 48 h to induce hypertrophy or fibrosis, which showed hypertrophic (increases in cellular size as well as the expression of ANP and BNP) or fibrotic features (increases in the expression of collagen Ⅰ, collagen Ⅲ, and α-SMA). Administration of magnolol and TG-101348 or JSI-124 (both JAK2 selective inhibitors) could prevent myocardial hypertrophy and fibrosis, accompanied by the decrease in the phosphorylation level of JAK2 and STAT3. Based on these observations, we conclude that magnolol can attenuate RV hypertrophy and fibrosis in hypoxia-induced PAH rats through a mechanism involving inhibition of the JAK2/STAT3 signaling pathway. Magnolol may possess the potential clinical value for PAH therapy.

scholarly journals Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway

2021 ◽  
Vol 22 (4) ◽  
pp. 1985
Author(s):  
Xiaohe Li ◽  
Ling Ma ◽  
Kai Huang ◽  
Yuli Wei ◽  
Shida Long ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
In Vivo Experiments ◽  
Age Related ◽  
And Migration ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-β1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-β1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway.

Abstract 218: Chemical Induced Reductive Stress Causes Cardiomyocyte Hypertrophy

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Sandeep B Shelar ◽  
Madhusudhanan Narasimhan ◽  
Gobinath Shanmugam ◽  
Neelu E Vargees ◽  
Ramasamy Sakthivel ◽  
...  
Keyword(s):  
Small Molecules ◽  
Cardiac Remodeling ◽  
Cell Types ◽  
Molecular Signature ◽  
Cardiomyocyte Hypertrophy ◽  
Reductive Stress ◽  
Vitro Model ◽  
C 50 ◽  
Sustained Activation

Background: Progressive accumulation of misfolded or unfolded proteins is a symbol of impaired proteostasis and proteotoxicity. Such a chronic proteotoxicity is amenable to cell types that are post mitotically matured with lack of further differentiation or proliferation. Our recent discovery using a mouse model of familial human cardiac disease displayed protuberant shift in the redox state towards reductive stress (RS) in association with accumulation of toxic protein aggregates. Further, sustained trans-activation of Nrf2/antioxidant signaling caused RS in the myopathy hearts. Accordingly, we hypothesized that whether profound activation of Nrf2/antioxidant signaling and subsequent RS may cause pathological remodeling in cardiomyocyte. The aim of this study was to investigate the effect of sustained pharmacological activation of Nrf2 on cardiac remodeling. Methods: HL1 cardiomyocytes were used as an in vitro model to study the RS-mediated cardiac remodeling. They were treated with 2-10 μM of potential Nrf2-inducers; sulforaphane (SF), di-methyl fumarate (DMF) and novel small molecules (C-38, C-50, C-63 and C-66) to establish RS by sustained activation of Nrf2/antioxidant signaling. Next, we investigated the implications of RS in cardiomyocyte remodeling by analyzing transcriptional and translational mechanisms using immunoblotting, qPCR, immunofluorescence, GSH and NADPH redox measurements in HL1 cells. Results: Dose dependent effects for individual small molecules including known Nrf2 inducers (SF and DMF) revealed distinct pro-reductive and reductive intracellular (i.e. reductive stress) environments. In fact, the obligatory activation of Nrf2 signaling was associated with significant upregulation of antioxidant enzymes and small molecular thiols including glutathione (GSH). Surprisingly, while pro-reductive condition in HL1 cells was subdued, the RS induced cardiomyocyte hypertrophy was evident from microscopic examination and molecular signature (increased expression of ANF and BNF) after 24-48 hrs of Nrf2 activation. Conclusion: In summary, the chemical induced sustained activation of Nrf2 leading to formation of reductive stress showed hypertrophic remodeling in HL1 cardiomyocytes.

Abstract 363: In Situ Cardiac Cellular Reprogramming Using Adenoviral Vectors: Implication for Clinical Myocardial Regeneration

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Megumi Mathison ◽  
Vivek P Singh ◽  
Maria J Chiuchiolo ◽  
Deepthi Sanagasetti ◽  
Yun Mao ◽  
...  
Keyword(s):  
Cardiac Fibroblasts ◽  
Lentiviral Vectors ◽  
Adenoviral Vectors ◽  
Cellular Reprogramming ◽  
Expression Vectors ◽  
Coronary Artery Ligation ◽  
Sprague Dawley ◽  
Artery Ligation ◽  
Lentivirus Vectors

Objective: The reprogramming of cardiac fibroblasts into induced cardiomyocytes (iCMs) improves ventricular function in myocardial infarction models. Only integrating chronic expression vectors have thus far been used to administer reprogramming genes, potentially limiting clinical applicability. We hypothesized that reprogramming could be achieved using non-integrating, acute expression adenoviral vectors. Methods: Adenoviral (Ad) and lentiviral vectors encoding Gata4 (G), Mef2c (M) and Tbx5 (T) were validated in vitro . Sprague Dawley rats then underwent coronary artery ligation and Ad-mediated administration of vascular endothelial growth factor to provide infarct prevascularization. Three weeks later, Ad or lentivirus encoding G, M, or T or an equivalent dose of a null vector was administered. Outcomes were analyzed by serial echocardiography, and by terminal MRI and histology. Results: Ad and lentivirus vectors provided equivalent in vitro GMT expression by Western blotting and AdGMT induced expression of the cardiomyocyte marker cTnT in approximately 7% of cardiac fibroblasts, compared to 4% of cells infected with LentiGMT. Sections of infarcted myocardium from rats that had been treated with AdGMT or LentiGMT demonstrated higher density of cells expressing the cardiomyocyte marker MHY7 compared to AdNull treated animals (p<0.05). Echocardiography demonstrated that AdGMT significantly increased ejection fraction compared to AdNull (AdGMT: 21% ± 3%, LentiGMT: 14% ± 5%, AdNull: -0.4% ± 2%; p<0.05). Conclusions: Adenoviral vectors are at least as effective as lentiviral vectors in inducing cardiac fibroblast transdifferentiation into iCMs and improving cardiac function in post-infarct rat hearts. The utility of short-term expression Ad vectors represents an important potential tool in inducing cardiac cellular reprogramming clinically.

scholarly journals Identification of Core Gene Biomarkers in Patients with Diabetic Cardiomyopathy

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Ning Li ◽  
Haiming Wu ◽  
Rongxin Geng ◽  
Qizhu Tang
Keyword(s):  
Western Blot ◽  
Diabetic Cardiomyopathy ◽  
Protein Level ◽  
Molecular Mechanisms ◽  
Cardiac Fibroblasts ◽  
Core Gene ◽  
Cardiomyocyte Hypertrophy ◽  
Diabetic Patients ◽  
Ppi Network

Diabetic cardiomyopathy (DCM) is a disorder of the myocardium in diabetic patients, which is one of the critical complications of diabetes giving rise to an increased mortality. However, the underlying mechanisms of DCM remain incompletely understood presently. This study was designed to screen the potential molecules and pathways implicated with DCM. GSE26887 involving 5 control individuals and 7 DCM patients was selected from the GEO database to identify the differentially expressed genes (DEGs). DAVID was applied to perform gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. A protein-protein interaction (PPI) network was also constructed to visualize the interactions among these DEGs. To further validate significant genes and pathways, quantitative real-time PCR (qPCR) and Western blot were performed. A total of 236 DEGs were captured, including 134 upregulated and 102 downregulated genes. GO, KEGG, and the PPI network disclosed that inflammation, immune disorders, metabolic disturbance, and mitochondrial dysfunction were significantly enriched in the development of DCM. Notably, IL6 was an upregulated hub gene with the highest connectivity degree, suggesting that it may interact with a great many molecules and pathways. Meanwhile, SOCS3 was also one of the top 15 hub genes in the PPI network. Herein, we detected the protein level of STAT3 and SOCS3 in a mouse model with DCM. Western blot results showed that the protein level of SOCS3 was significantly lower while phosphorylated-STAT3 (P-STAT3) was activated in mice with DCM. In vitro results also uncovered the similar alterations of SOCS3 and P-STAT3 in cardiomyocytes and cardiac fibroblasts induced by high glucose (HG). However, overexpression of SOCS3 could significantly reverse HG-induced cardiomyocyte hypertrophy and collagen synthesis of cardiac fibroblasts. Taken together, our analysis unveiled potential biomarkers and molecular mechanisms in DCM, which could be helpful to the diagnosis and treatment of DCM.

scholarly journals Targeting neuropilin-1 suppresses the stability of CD4+CD25+ regulatory T cells via the NF-κB signaling pathway in sepsis

2020 ◽  
Author(s):  
Yu-lei Gao ◽  
Chun-xue Wang ◽  
Zi-yi Wang ◽  
Wen-jie Li ◽  
Yan-cun Liu ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Signaling Pathway ◽  
Binding Activity ◽  
Dna Binding Activity ◽  
Sepsis Model ◽  
The Stability ◽  
The Impact ◽  
Tgf Β1

Neuropilin (Nrp)-1 contributes to maintain the stability of CD4+CD25+ regulatory T cells (Tregs). We investigated the impact of Nrp-1 on the stability of CD4+CD25+ Tregs, and the underlying signaling pathways, in a sepsis model. Splenic CD4+CD25+ Tregs were treated with anti-Nrp-1, or transfected to silence Nrp-1 and ikkβ, or administered with PDTC, followed by rSema3A in sepsis simulation. After creation of a sepsis model in mice, anti-Nrp-1 was administered. Expression of foxp3- TSDR, apoptosis rate, Foxp-3/CTLA-4/TGF-β1, IL-10 and TGF-β1, and NF-κB signaling activity of CD4+CD25+ Tregs were determined. Sepsis simulation with or without rSema3A increased the stability of CD4+CD25+ Tregs, including an increase in the expression of Foxp-3/CTLA-4/TGF-β1, decrease in apoptosis and methylation of foxp3- TSDR, increase in the secretion of TGF-β1 and IL-10, and increase in the immunosuppressive effect on CD4+T lymphocytes. silencing of Nrp-1 or anti-Nrp-1 treatment interdicted LPS stimulation with or without a rSema3A-mediated effect. Sepsis simulation increased the DNA-binding activity of NF-κB, as well as the p-ikkβ/ikkβ and p-P65/P65 ratios in vitro and vivo. Silencing of ikkβ expression or PDTC treatment suppressed the stability of CD4+CD25+ Tregs in LPS-induced sepsis. Weakening Nrp-1 reduced the stability of CD4+CD25+ Tregs by regulating the NF-κB signaling pathway, and could be a new target for immunoregulation in sepsis.

scholarly journals GSTA3 regulates TGF-β1-induced renal interstitial fibrosis in NRK-52E cells as a component of the PI3K–Keap1/Nrf2 pathway

2019 ◽  
Vol 47 (11) ◽  
pp. 5787-5801
Author(s):  
Yun Xiao ◽  
Zhiwei Zhang ◽  
Yingyu Fu ◽  
Huizhi Shan ◽  
Sini Cui ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Interstitial Fibrosis ◽  
Mapk Pathway ◽  
Mrna Levels ◽  
Renal Interstitial Fibrosis ◽  
Nrf2 Pathway ◽  
Nrf2 Signaling Pathway ◽  
Nrf2 Expression ◽  
Tgf Β1

Objective To evaluate the effect of GSTA3 within the PI3K–Keap1/Nrf2 pathway in renal interstitial fibrosis (RIF). Methods An in vitro RIF model with TGF-β1 stimulation in NRK-52E cells was established to identify potential signaling pathways that modulate GSTA3. Changes in GSTA3 expression were observed in the RIF model after silencing or enhancing Nrf2 expression. Changes in GSTA3, Keap1, and Nrf2 expression were detected after blocking the upstream of the Keap1/Nrf2 signaling pathway (including MAPK and PI3K/Akt). The effect of Nrf2 on GSTA3 expression was evaluated by overexpressing Nrf2. Results Protein and mRNA levels of GSTA3, FN, Nrf2, and Keap1 were significantly increased after TGF-β1 stimulation. GSTA3 was also upregulated following overexpression of Nrf2. TGF-β1 activated the PI3K/Akt signaling pathway, leading to RIF. After blocking this pathway, the production of superoxide dismutase, reactive oxygen species, and fibronectin were reduced. The MAPK pathway was not involved in the development of RIF via regulating GSTA3 expression. Conclusions The PI3K–KEAP1/Nrf2–GSTA3 signaling pathway is a possible mechanism of resisting external stimulation of renal fibrosis factors, regulating oxidative stress, and preventing RIF.

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