Salvianolate reduces atrial fibrillation through suppressing atrial interstitial fibrosis by inhibiting TGF-β1/Smad2/3 and TXNIP/NLRP3 inflammasome signaling pathways in post-MI rats

Abstract Background: Sacubitril/valsartan (SAC/VAL), combined inhibitors of angiotensin receptor (AT-R) and neprilysin receptor, prevents Angiotensin Ⅱ (AngⅡ) from binding AT1-R and blocks degradation of natriuretic peptides. Despite its efficacy in reducing ventricular fibrosis and preserving cardiac functions, which has been extensively demonstrated in myocardial infarction or pressure overload models, few studies have been conducted to determine whether SAC/VAL could attenuate atrial fibrosis and decrease atrial fibrillation (AF) susceptibility. Methods: Sprague-Dawley rats were divided into three groups after implantation of an osmotic pump preloaded with AngⅡ and received corn oil, VAL, or SAC/VAL treatment for 28 days. Electrophysiological study was performed to determine inducibility and duration of AF. Echocardiography was performed before and 28 days after osmotic mini-pump implantation to evaluate cardiac functions. Enzyme-linked immunosorbent assay was perfomed to detect the serum concentration of atrial natriuretic peptide (ANP), N-terminal pro-brain natriuretic peptide (NT-proBNP) and AngⅡ. Masson staining was performed to determine the extent of interstitial fibrosis. Immunohistochemical, and immunofluorescence staining as well as transwell and MTT assay were also performed. Western blot analysis was perfomed to figure out how SAC/VAL exerts its anti-fibrosis effects in atriums.Results: After 28 days of AngⅡ stimulation, rats in SAC/VAL group exhibited reduced reduced extent of atrial fibrosis, inhibited proliferation, migration, and differentiation of atrial fibroblasts and decreased susceptibility to atrial fibrillation. We further found that SAC/VAL exerted its effect on AngⅡ-induced atrial fibrosis by inhibiting the p-Smad2/3, p-JNK, and p-p38 MAPK signaling pathways in vivo. Conclusions: Our study provided experimental evidence for the inhibition of atrial fibrosis and reduced susceptibility to AF by SAC/VAL. These results emphasize the importance of SAC/VAL in the prevention of AngⅡ-induced atrial fibrosis and may help to enrich the options for atrial fibrillation pharmacotherapy.

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Salidroside Ameliorates Renal Interstitial Fibrosis by Inhibiting the TLR4/NF-κB and MAPK Signaling Pathways

International Journal of Molecular Sciences ◽

10.3390/ijms20051103 ◽

2019 ◽

Vol 20 (5) ◽

pp. 1103 ◽

Cited By ~ 8

Author(s):

Rui Li ◽

Yujuan Guo ◽

Yiming Zhang ◽

Xue Zhang ◽

Lingpeng Zhu ◽

...

Keyword(s):

Signaling Pathways ◽

Inflammatory Cytokines ◽

Renal Fibrosis ◽

Interstitial Fibrosis ◽

Mapk Signaling ◽

Renal Interstitial Fibrosis ◽

Mapk Signaling Pathways ◽

Tgf Β1

Salidroside (Sal) is an active ingredient that is isolated from Rhodiola rosea, which has been reported to have anti-inflammatory activities and a renal protective effect. However, the role of Sal on renal fibrosis has not yet been elucidated. Here, the purpose of the current study is to test the protective effects of Sal against renal interstitial fibrosis (RIF), and to explore the underlying mechanisms using both in vivo and in vitro models. In this study, we establish the unilateral ureteric obstruction (UUO) or folic acid (FA)-induced mice renal interstitial fibrosis in vivo and the transforming growth factor (TGF)-β1-stimulated human proximal tubular epithelial cell (HK-2) model in vitro. The levels of kidney functional parameters and inflammatory cytokines in serum are examined. The degree of renal damage and fibrosis is determined by histological assessment. Immunohistochemistry and western blotting are used to determine the mechanisms of Sal against RIF. Our results show that treatment with Sal can ameliorate tubular injury and deposition of the extracellular matrix (ECM) components (including collagen Ш and collagen I). Furthermore, Sal administration significantly suppresses epithelial-mesenchymal transition (EMT), as evidenced by a decreased expression of α-SMA, vimentin, TGF-β1, snail, slug, and a largely restored expression of E-cadherin. Additionally, Sal also reduces the levels of serum biochemical markers (serum creatinine, Scr; blood urea nitrogen, BUN; and uric acid, UA) and decreases the release of inflammatory cytokines (IL-1β, IL-6, TNF-α). Further study revealed that the effect of Sal on renal interstitial fibrosis is associated with the lower expression of TLR4, p-IκBα, p-NF-κB and mitogen-activated protein kinases (MAPK), both in vivo and in vitro. In conclusion, Sal treatment improves kidney function, ameliorates the deposition of the ECM components and relieves the protein levels of EMT markers in mouse kidneys and HK-2 cells. Furthermore, Sal treatment significantly decreases the release of inflammatory cytokines and inhibits the TLR4/NF-κB and MAPK signaling pathways. Collectively, these results suggest that the administration of Sal could be a novel therapeutic strategy in treating renal fibrosis.

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Urolithin A attenuates renal fibrosis by inhibiting TGF-β1/Smad and MAPK signaling pathways

Journal of Functional Foods ◽

10.1016/j.jff.2021.104547 ◽

2021 ◽

Vol 83 ◽

pp. 104547

Author(s):

Zhenzhen Cheng ◽

Jingjing Tu ◽

Hongpan Zhang ◽

Yi zhang ◽

Benhong Zhou

Keyword(s):

Signaling Pathways ◽

Renal Fibrosis ◽

Mapk Signaling ◽

Urolithin A ◽

Mapk Signaling Pathways ◽

Tgf Β1

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The crosstalk between cardiomyocyte calcium and inflammasome signaling pathways in atrial fibrillation

Pflügers Archiv - European Journal of Physiology ◽

10.1007/s00424-021-02515-4 ◽

2021 ◽

Author(s):

Xiaolei Wang ◽

Xiaohui Chen ◽

Dobromir Dobrev ◽

Na Li

Keyword(s):

Atrial Fibrillation ◽

Signaling Pathways

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Regulation of myofibroblast differentiation by convergence of the Wnt and TGF-β1/Smad signaling pathways

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2009.02.008 ◽

2009 ◽

Vol 46 (5) ◽

pp. 610-611 ◽

Cited By ~ 12

Author(s):

Sarah Jane George

Keyword(s):

Signaling Pathways ◽

Myofibroblast Differentiation ◽

Smad Signaling ◽

Tgf Β1

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Increased α-Actinin-2 Expression in the Atrial Myocardium of Patients with Atrial Fibrillation Related to Rheumatic Heart Disease

Cardiology ◽

10.1159/000446362 ◽

2016 ◽

Vol 135 (3) ◽

pp. 151-159 ◽

Cited By ~ 3

Author(s):

Lei Zhang ◽

Nan Zhang ◽

Xuejiao Tang ◽

Fajin Liu ◽

Suxin Luo ◽

...

Keyword(s):

Atrial Fibrillation ◽

Heart Disease ◽

Sinus Rhythm ◽

Rheumatic Heart Disease ◽

Collagen Content ◽

Atrial Fibrosis ◽

Smad Pathway ◽

Smad Signaling Pathway ◽

Tgf Β1 ◽

Rheumatic Heart

Objectives: Atrial ﬁbrosis, a marker of atrial structural remodeling, plays a critical role in atrial ﬁbrillation (AF). α- Actinin-2 is associated with structural remodeling related to stretching. The transforming growth factor-β1 (TGF-β1)/Smad pathway plays an important role in atrial fibrosis. We investigated the effects of the TGF-β1/Smad signaling pathway on α-actinin-2 in atrial fibrosis in patients with AF. Methods: Forty-one right atrial specimens obtained from patients with rheumatic heart disease (RHD) were divided into a chronic (c)AF group, i.e. RHD + cAF (n = 29), and a sinus rhythm group, i.e. RHD + sinus rhythm (n = 12). Patients with congenital heart disease (CHD) and sinus rhythm who underwent heart surgery served as controls (n = 10). Fibrosis was assessed by histological examination, and expression of α-actinin-2, TGF-β1 and Smad2/phosphorylated Smad2 (p-Smad2) was evaluated by immunohistochemistry, quantitative real-time PCR and Western blotting. In rat atrial fibroblasts treated with TGF-β1, the collagen content was measured using hydroxyproline detection, and α-actinin-2 and p-Smad2 were evaluated by semiquantitative reverse-transcription PCR and Western blotting. Results: The histology results revealed a significant increase in atrial fibrosis in AF patients. The collagen content, mRNA and protein expression levels of α-actinin-2 and the components of the TGF-β1/Smad signaling pathway were significantly gradually increased in the CHD + sinus rhythm, RHD + sinus rhythm and RHD + cAF groups (p < 0.05). The mRNA and protein levels of α-actinin-2 and TGF-β1 in RHD patients were positively correlated with the collagen volume fraction. A positive correlation between the expression of α-actinin-2 and TGF-β1 was also observed. In rat atrial fibroblasts treated with TGF-β1, the collagen content was greater than that in the control group (p < 0.05), and the expression levels of α- actinin-2 and p-Smad2 were also upregulated (p < 0.05). Conclusions: α-Actinin-2 expression was increased in the atrial tissues of patients with AF secondary to RHD. α-Actinin-2 was upregulated via the TGF-β1/Smad pathway in atrial fibroblasts, which suggests that it may be involved in TGF-β1/Smad pathway-induced atrial fibrosis in patients with AF.

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Chalcone flavokawain A attenuates TGF ‐β1‐induced fibrotic pathology via inhibition of ROS /Smad3 signaling pathways and induction of Nrf2/ ARE ‐mediated antioxidant genes in vascular smooth muscle cells

Journal of Cellular and Molecular Medicine ◽

10.1111/jcmm.13973 ◽

2018 ◽

Vol 23 (2) ◽

pp. 775-788 ◽

Cited By ~ 4

Author(s):

You‐Cheng Hseu ◽

Ting‐Yu Yang ◽

Mei‐Ling Li ◽

Peramaiyan Rajendran ◽

Dony Chacko Mathew ◽

...

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Signaling Pathways ◽

Vascular Smooth Muscle Cells ◽

Muscle Cells ◽

Antioxidant Genes ◽

Tgf Β1

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TGF-β1 targets Smad, p38 MAPK, and PI3K/Akt signaling pathways to induce PFKFB3 gene expression and glycolysis in glioblastoma cells

FEBS Journal ◽

10.1111/febs.14201 ◽

2017 ◽

Vol 284 (20) ◽

pp. 3437-3454 ◽

Cited By ~ 41

Author(s):

Ana Rodríguez-García ◽

Paula Samsó ◽

Pere Fontova ◽

Helga Simon-Molas ◽

Anna Manzano ◽

...

Keyword(s):

Gene Expression ◽

Signaling Pathways ◽

P38 Mapk ◽

Akt Signaling ◽

Glioblastoma Cells ◽

Tgf Β1

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Potential Mechanism Prediction of Herbal Medicine for Pulmonary Fibrosis Associated with SARS-CoV-2 Infection Based on Network Analysis and Molecular Docking

Frontiers in Pharmacology ◽

10.3389/fphar.2021.602218 ◽

2021 ◽

Vol 12 ◽

Author(s):

De Jin ◽

Xuedong An ◽

Yuqing Zhang ◽

Shenghui Zhao ◽

Liyun Duan ◽

...

Keyword(s):

Molecular Docking ◽

Pulmonary Fibrosis ◽

Signaling Pathways ◽

Topological Analysis ◽

Recovery Period ◽

Treatment Protocol ◽

Docking Simulation ◽

Mapk Signaling ◽

Tnf Α ◽

Tgf Β1

Background: Coronavirus Disease 2019 (COVID-19) is still a relevant global problem. Although some patients have recovered from COVID-19, the sequalae to the SARS-CoV-2 infection may include pulmonary fibrosis, which may contribute to considerable economic burden and health-care challenges. Convalescent Chinese Prescription (CCP) has been widely used during the COVID-19 recovery period for patients who were at high risk of pulmonary fibrosis and is recommended by the Diagnosis and Treatment Protocol for COVID-19 (Trial Version sixth, seventh). However, its underlying mechanism is still unclear.Methods: In this study, an integrated pharmacology approach was implemented, which involved evaluation of absorption, distribution, metabolism and excretion of CCP, data mining of the disease targets, protein-protein interaction (PPI) network construction, and analysis, enrichment analysis, and molecular docking simulation, to predict the bioactive components, potential targets, and molecular mechanism of CCP for pulmonary fibrosis associated with SARS-CoV-2 infection.Results: The active compound of CCP and the candidate targets, including pulmonary fibrosis targets, were obtained through database mining. The Drug-Disease network was constructed. Sixty-five key targets were identified by topological analysis. The findings of Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation suggested that the VEGF, Toll-like 4 receptor, MAPK signaling pathway, and TGF-β1 signaling pathways may be involved in pulmonary fibrosis. In the molecular docking analyses, VEGF, TNF-α, IL-6, MMP9 exhibited good binding activity. Findings from our study indicated that CCP could inhibit the expression of VEGF, TNF-α, IL-6, MMP9, TGF-β1 via the VEGF, Toll-like 4 receptor, MAPK, and TGF-β1 signaling pathways.Conclusion: Potential mechanisms involved in CCP treatment for COVID-19 pulmonary fibrosis associated with SARS-CoV-2 infection involves multiple components and multiple target points as well as multiple pathways. These findings may offer a profile for further investigations of the anti-fibrotic mechanism of CCP.

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