Hepatocyte growth factor and basic fibroblast growth factor regulate atrial fibrosis in patients with atrial fibrillation and rheumatic heart disease via the mitogen-activated protein kinase signaling pathway

Li, Mingjiang; Yi, Xin; Ma, Lele; Zhou, Yanli

doi:10.3892/etm.2013.1274

Cited by 29 publications

(20 citation statements)

References 34 publications

(27 reference statements)

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“…Selected prior studies suggest that cardiac FGF-2 expression is pro-fibrotic. Li and colleagues documented elevated FGF-2 in fibrotic human atria inferring a pro-fibrotic causative role for FGF-2 [ 25 ]. In addition, Virag and co-workers detected greater infarct scar formation after cardiac-specific over-expression of FGF-2 in post-MI mutant mice [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor-2 regulates human cardiac myofibroblast-mediated extracellular matrix remodeling

et al. 2015

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BackgroundTissue fibrosis and chamber remodeling is a hallmark of the failing heart and the final common pathway for heart failure of diverse etiologies. Sustained elevation of pro-fibrotic cytokine transforming growth factor-beta1 (TGFβ1) induces cardiac myofibroblast-mediated fibrosis and progressive structural tissue remodeling.ObjectivesWe examined the effects of low molecular weight fibroblast growth factor (LMW-FGF-2) on human cardiac myofibroblast-mediated extracellular matrix (ECM) dysregulation and remodeling.MethodsHuman cardiac biopsies were obtained during open-heart surgery and myofibroblasts were isolated, passaged, and seeded within type I collagen matrices. To induce myofibroblast activation and ECM remodeling, myofibroblast-seeded collagen gels were exposed to TGFβ1. The extent of ECM contraction, myofibroblast activation, ECM dysregulation, and cell apoptosis was determined in the presence of LMW-FGF-2 and compared to its absence. Using a novel floating nylon-grid supported thin collagen gel culture platform system, myofibroblast activation and local ECM remodeling around isolated single cells was imaged using confocal microscopy and quantified by image analysis.ResultsTGFβ1 induced significant myofibroblast activation and ECM dysregulation as evidenced by collagen gel contraction, structural ECM remodeling, collagen synthesis, ECM degradation, and altered TIMP expression. LMW-FGF-2 significantly attenuated TGFβ1 induced myofibroblast-mediated ECM remodeling. These observations were similar using either ventricular or atrial-derived cardiac myofibroblasts. In addition, for the first time using individual cells, LMW-FGF-2 was observed to attenuate cardiac myofibroblast activation and prevent local cell-mediated ECM perturbations.ConclusionsLMW-FGF-2 attenuates human cardiac myofibroblast-mediated ECM remodeling and may prevent progressive maladaptive chamber remodeling and tissue fibrosis for patients with diverse structural heart diseases.

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Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor-2 regulates human cardiac myofibroblast-mediated extracellular matrix remodeling

et al. 2015

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“…At present, there are few studies on the signaling pathways related to the pathogenesis of RHD, and there are only 6 signaling pathways with signi cant research progress: RhoA/Rho-dependent kinase (RhoA/ROCK) signaling pathway,Mitogen-activated protein kinase (MAPK) signaling pathway Protein kinase B/S6 kinase (AKT/S6K) signaling pathway TGF-β1/Smad signaling pathway Wnt signaling pathway and S1PR1/STAT3 signaling pathway [34,[51][52][53][54][55]. And there are only three potential intervention targets found in these signaling pathway studies: Intervene in the expression of interferon (IFN)-γ and tumour necrosis factor (TNF)-α to regulate extracellular matrix remodeling to reduce heart damage caused by RHD; Intervene in AKT/S6K signaling pathway to inhibit TGF-β1-induced broblasts; Intervene in the S1PR1/STAT3 signaling pathway to reduce RHDinduced valvular damage.…”

Section: Discussionmentioning

confidence: 99%

Intervening in the S1PR1/STAT3 Signaling Pathway Attenuates Valvular Damage Due to Rheumatic Heart Disease

Xian

Chen

et al. 2020

Preprint

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Background: Rheumatic heart disease (RHD) affects many patients every year, but its pathogenesis is still unclear. Recent studies have found that the sphingosine 1-phosphate receptor 1 (S1PR1)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is involved in valvular damage by promoting the differentiation of T helper 17 (Th17) cells during the development of valvular damage caused by RHD. In this work, we investigated whether altering the S1PR1/STAT3 signaling pathway attenuates valvular damage due to RHD. Methods: Inactivated Group A streptococci (GAS) was used to establish the RHD rat model. Recombinant adeno-associated virus (serotype 9) vectors carrying the S1PR1 overexpression sequence was used to overexpress the expression of S1PR1. STAT3-small interfering RNA (STAT3-siRNA) was used to inhibit the expression of STAT3. Reverse transcription-quantitative PCR (RT-qPCR) was used to detect the mRNA expression of S1PR1, STAT3, collagen type III α1 chain (Col3a1) and fibroblast-specific protein 1 (FSP1). Western blotting (WB) and immunohistochemistry were used to detect the protein expression of S1PR1, STAT3, phosphorylated (p-) STAT3, retinoic acid-related orphan receptor gamma T (RORγt). Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were used to detect the levels of interleukin (IL)-6 and IL-17. Haematoxylin and eosin (H&E) staining and Sirius red staining were used to evaluate the degree of inflammation and fibrosis in valve tissues.Results: The expression of S1PR1 in valve tissues of RHD model rats was decreased. The levels of IL-6 and IL-17 in valves and serum of RHD model rats were increased as well as an increase of p-STAT3. The degree of valvular inflammation and fibrosis of RHD model rats was increased. Overexpression of S1PR1 and Inhibition of STAT3 overexpressed S1PR1 expression and decreased STAT3 expression respectively and reduced the total amount of p-STAT3, resulting in decreased expression of IL-6, IL-17 and RORγt and reduced the degree of valvular inflammatory and fibrosis. Conclusions: These results suggest that the S1PR1/STAT3 signaling pathway is involved in regulating the Th17 cell-related cytokines during the vavular damage due to RHD, and altering the S1PR1/STAT3 signaling pathway could affect the expression of Th17 cell-related cytokines then attenuate the vavular damage due to RHD.

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“…Atrial fibrillation (AF) is becoming more common in patients with cardiovascular diseases, including rheumatic heart disease (RHD), hypertension, coronary heart disease, congenital heart disease, cardiomyopathy and pericardial disease ( 1 ). Atrial fibrillation can severely affect human health; rapid ventricular rates may result in the development of fatal malignant arrhythmia, such as ventricular fibrillation ( 1 ). Another condition induced by AF is mural thrombus, which may lead to the development of major adverse cardiovascular events, including acute myocardial infarction and stroke ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

Snail1 is positively correlated with atrial fibrosis in patients with atrial fibrillation and rheumatic heart disease

Guo

et al. 2017

Exp Ther Med

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The present study investigated the association between Snail1 and atrial fibrosis in patients with atrial fibrillation (AF) and rheumatic heart disease (RHD) and to determine the possible mechanism underlying this interrelation. A total of 19 patients were included in the current study and were divided into two groups: A sinus rhythm (SR) group (n=9) and an AF group (n=10). All patients underwent heart valve replacement surgery, during which ~200 mg right atrium tissue was obtained. Hematoxylin and eosin and Masson's trichrome-stained sections were used to evaluate the morphological changes of cardiomyocytes and the level of fibrosis. Immunohistochemistry was applied to observe the location and expression of Snail1. Reverse transcription-quantitative polymerase chain reaction was used to measure Snail1 mRNA levels. Western blotting was used to determine changes in the expression of Snail1, as well as in the expression of proteins involved in the Wnt pathway, including Wnt1, Wnt 3a, Wnt8a, Wnt5a and Wnt11. Compared with the SR group, expanded cardiomyocytes and higher collagen deposition was detected in the atrial tissue of the AF group. The expression of Snail1 mRNA and protein was significantly higher in the AF group than in the SR group (P<0.05). Additionally, the expression of Wnt1, 3a and 8a in the canonical Wnt signaling pathway, and Wnt5a and 11 in the noncanonical Wnt signaling pathway were significantly increased in the AF group. Furthermore, the phosphorylation level of glycogen synthase kinase 3β (GSK3β) and the levels of β-catenin and GSK3β were significantly increased in the AF group compared with the SR group (P<0.05). Snail1 may be involved in the development and maintenance of atrial fibrosis in patients with atrial fibrillation and rheumatic heart disease and may be developed as a novel biomarker to evaluate myocardial fibrosis in the future. Additionally, the current study suggests that the Wnt signaling pathway may participate in the process of increased Snail1 expression and atrial fibrosis in patients with AF and RHD.

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Hepatocyte growth factor and basic fibroblast growth factor regulate atrial fibrosis in patients with atrial fibrillation and rheumatic heart disease via the mitogen-activated protein kinase signaling pathway

Cited by 29 publications

References 34 publications

Fibroblast growth factor-2 regulates human cardiac myofibroblast-mediated extracellular matrix remodeling

Fibroblast growth factor-2 regulates human cardiac myofibroblast-mediated extracellular matrix remodeling

Intervening in the S1PR1/STAT3 Signaling Pathway Attenuates Valvular Damage Due to Rheumatic Heart Disease

Snail1 is positively correlated with atrial fibrosis in patients with atrial fibrillation and rheumatic heart disease

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