Smad3 Signaling Critically Regulates Fibroblast Phenotype and Function in Healing Myocardial Infarction

Dobaczewski, Marcin; Bujak, Marcin; Li, Na; González-Quesada, Carlos; Mendoza, Leonardo H.; Wang, Xaiao Fan; Frangogiannis, Nikolaos G.

doi:10.1161/circresaha.109.216101

Cited by 341 publications

(310 citation statements)

References 38 publications

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“…18,42 TGF-b is thought to be one of the molecules capable of facilitating fibrosis of different tissues and organs. [42][43][44] A solid capsule is commonly recognized in cultures under hydrodynamic stimuli probably because chondrocytes located at the edge of constructs have a flattened, elongated shape, and thus become fibroblast-like 6 such that more collagen I, but less GAG are produced. 45,46 We also reported that sufficient fibrosis-promoting factors are necessary for the capsule formation even in hydrodynamic cultivation.…”

Section: Discussionmentioning

confidence: 99%

Differential Morphology and Homogeneity of Tissue-Engineered Cartilage in Hydrodynamic Cultivation with Transient Exposure to Insulin-Like Growth Factor-1 and Transforming Growth Factor-β1

Yang

Barabino

2013

Tissue Engineering Part A

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Successful tissue-engineering strategies for cartilage repair must maximize the efficacy of chondrocytes within their limited life span. To that end, the combination of exogenous growth factors with mechanical stimuli holds promise for development of clinically relevant cartilage tissue substitutes. The current study aimed to determine whether incorporation of transient exposure to growth factors into a hydrodynamic bioreactor system can improve the functional maturation of tissue-engineered cartilage. Chondrocyte-seeded polyglycolic acid scaffolds were cultivated within a wavy-walled bioreactor that imparts fluid flow-induced shear stress for 4 weeks. Constructs were nourished with 100 ng/mL insulin-like growth factor-1 (IGF-1) or 10 ng/mL transforming growth factor-b1 (TGF-b1) either for the first 15 days of the culture (transient) or throughout the entire cultivation (continuous). Transiently treated constructs were found to exhibit better functional properties than continuously nourished constructs. The limited development of engineered tissues continuously stimulated by IGF-1 or TGF-b1 was related to massive growth factor leftovers in the environments that downregulated the expression of the associated receptors. Treatment with TGF-b1 eliminated the formation of a fibrous capsule at the construct periphery possibly through suppression of Smad3 phosphorylation, yielding constructs with greater homogeneity. Furthermore, TGF-b1 reversely regulated Smad2 and Smad3 pathways in articular chondrocytes under hydrodynamic stimuli partially via Smad7. Collectively, transient exposure to growth factors is likely to maintain chondrocyte homeostasis, and thus promotes their anabolic activities under hydrodynamic stimuli. The present work suggests that robust hydrodynamically engineered neocartilage with a reduced fibrotic response and enhanced tissue homogeneity can be achieved through optimization of growth factor supplementation protocols and potentially through manipulation of intracellular signals such as Smad.

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Section: Discussionmentioning

confidence: 99%

Differential Morphology and Homogeneity of Tissue-Engineered Cartilage in Hydrodynamic Cultivation with Transient Exposure to Insulin-Like Growth Factor-1 and Transforming Growth Factor-β1

Yang

Barabino

2013

Tissue Engineering Part A

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“…Moreover, TGF-β markedly and consistently stimulates synthesis of extracellular matrix proteins (such as collagen I, collagen III and fibronectin) (75,76) and promotes a matrix-preserving program by decreasing collagenase expression and by accentuating tissue inhibitor of metalloproteinases (TIMP)1 expression (38,77). In contrast, effects of TGF-β on cardiac fibroblast proliferation are less consistent: both proliferative and antiproliferative effects have been reported (76,78). Differences in TGF-β concentration, and in the experimental context may account for the conflicting observations.…”

Section: Tgf-β In Regulation Of Fibroblast Phenotype and Functionmentioning

confidence: 99%

“…In vitro experiments showed that Smad3 null cardiac fibroblasts were hyperproliferative, but exhibited impaired function. Smad3 was critically involved in myofibroblast transdifferentiation and mediated TGF-β-induced extracellular matrix synthesis and TIMP upregulation (38,76). Considering the broad effects of Smad3 on all cell types, it is unclear whether the improved remodeling exhibited by mice with global loss of Smad3 is due to fibroblast-mediated actions.…”

Section: Tgf-β Signaling Pathways In the Infarcted Myocardiummentioning

confidence: 99%

“…CCN2 may synergize with TGF-β to stimulate cardiomyocyte hypertrophy (119) and enhance fibrosis (76). Although transgenic overexpression studies have suggested protective effects of CCN2 on the size of the infarct (120), actions of endogenous CCN2 in the infarcted myocardium have not been dissected.…”

Section: Tgf-β Signaling Pathways In the Infarcted Myocardiummentioning

confidence: 99%

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The role of transforming growth factor (TGF)-β in the infarcted myocardium

Frangogiannis

2017

J. Thorac. Dis.

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119

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The adult mammalian heart has negligible regenerative capacity. Following myocardial infarction, sudden necrosis of cardiomyocytes triggers an intense inflammatory reaction that clears the wound from dead cells and matrix debris, while activating a reparative program. A growing body of evidence suggests that members of the transforming growth factor (TGF)-β family critically regulate the inflammatory and reparative response following infarction. Although all three TGF-β isoforms (TGF-β1, -β2 and -β3) are markedly upregulated in the infarcted myocardium, information on isoform-specific actions is limited.Experimental studies have suggested that TGF-β exerts a wide range of actions on cardiomyocytes, fibroblasts, immune cells, and vascular cells. The findings are often conflicting, reflecting the contextdependence of TGF-β-mediated effects; conclusions are often based exclusively on in vitro studies and on associative evidence. TGF-β has been reported to modulate cardiomyocyte survival responses, promote monocyte recruitment, inhibit macrophage pro-inflammatory gene expression, suppress adhesion molecule synthesis by endothelial cells, promote myofibroblast conversion and extracellular matrix synthesis, and mediate both angiogenic and angiostatic effects. This review manuscript discusses our understanding of the cell biological effects of TGF-β in myocardial infarction. We discuss the relative significance of downstream TGF-β-mediated Smad-dependent and -independent pathways, and the risks and challenges of therapeutic TGF-β targeting. Considering the high significance of TGF-β-mediated actions in vivo, study of cell-specific effects and dissection of downstream signaling pathways are needed in order to design safe and effective therapeutic approaches.

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“…TGF-β1 is a key mediator of the differentiation of fibroblasts to myofibroblasts (14), and this TGF-β1-induced effect has been demonstrated to be associated with the Smad2 and p38 mitogen-activated protein kinase (MAPK) signaling pathways (15)(16)(17) that curcumin has an inhibitory effect on ECM secretion in cultured CFs (10), the effect of curcumin on the differentiation of CFs and the underlying mechanisms are yet to be fully elucidated. In the present study, using cultured CFs from neonatal rats, it was demonstrated that curcumin has an inhibitory effect on TGF-β1-induced cardiac fibroblast differentiation.…”

Section: Introductionmentioning

confidence: 99%

Curcumin suppresses transforming growth factor-β1-induced cardiac fibroblast differentiation via inhibition of Smad-2 and p38 MAPK signaling pathways

Liu

Shi

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. The differentiation of cardiac fibroblasts (CFs) into myofibroblasts and the subsequent deposition of the extracellular matrix is associated with myocardial fibrosis following various types of myocardial injury. In the present study, the effect of curcumin, which is a pharmacologically-safe natural compound from the Curcuma longa herb, on transforming growth factor (TGF)-β1-induced CFs was investigated, and the underlying molecular mechanisms were examined. The expression levels of α-smooth muscle actin (SMA) stress fibers were investigated using western blotting and immunofluorescence in cultured neonatal rat CFs. Protein and mRNA expression levels of α-SMA and collagen type I (ColI) were determined by western blotting and reverse transcription-quantitative polymerase chain reaction. In addition, the activation of Smad2 and p38 was examined using western blotting. Curcumin, SB431542 (a TGF-βR-Smad2 inhibitor) and SB203580 (a p38 inhibitor) were used to inhibit the stimulation by TGF-β1. The results demonstrated that the TGF-β1-induced expression of α-SMA and ColI was suppressed by curcumin at the mRNA and protein levels, while SB431542 and SB203580 induced similar effects. Furthermore, phosphorylated Smad-2 and p38 were upregulated in TGF-β1-induced CFs, and these effects were substantially inhibited by curcumin administration. In conclusion, the results of the present study demonstrated that treatment with curcumin effectively suppresses TGF-β1-induced CF differentiation via Smad-2 and p38 signaling pathways. Thus, curcumin may be a potential therapeutic agent for the treatment of cardiac fibrosis. IntroductionCardiac fibroblast differentiation, excessive biosynthesis and destruction of the interstitial extracellular matrix (ECM) in the ventricles of the heart are key features of cardiac fibrosis, which is a consequence of cardiac remodeling initiated by pathological events associated with various cardiovascular disorders (1). Induced by transforming growth factor (TGF)-β1 and other factors, cardiac fibroblasts (CFs) differentiate into α-smooth muscle actin (SMA) fiber-rich cardiac myofibroblasts that facilitate contractility and increase ECM modulation ability (1). Although these changes are important for wound repair and are beneficial for the maintenance of cardiac function, continuous myocardial fibrosis may result in abnormal myocardial stiffness and, ultimately, ventricular dysfunction (1).Curcumin, 1,7-bis(4-hydroxy-3-methoxyphenyl)-1, 6-heptadiene-3,5-dione, is a natural polyphenolic compound from the Curcuma longa herb, possessing multiple biological and medicinal activities (2). The pharmacological safety of curcumin has previously been demonstrated in various animal models, and curcumin is nontoxic even at high doses (3). Previous studies have demonstrated that curcumin has antioxida, anti-inflammatory, anti-proliferative, pro-apoptotic and anti-carcinogenic properties (4-8). Furthermore, previous investigations into the effects of curcumin in heart disease have indicated that curcumin has...

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Smad3 Signaling Critically Regulates Fibroblast Phenotype and Function in Healing Myocardial Infarction

Cited by 341 publications

References 38 publications

Differential Morphology and Homogeneity of Tissue-Engineered Cartilage in Hydrodynamic Cultivation with Transient Exposure to Insulin-Like Growth Factor-1 and Transforming Growth Factor-β1

Differential Morphology and Homogeneity of Tissue-Engineered Cartilage in Hydrodynamic Cultivation with Transient Exposure to Insulin-Like Growth Factor-1 and Transforming Growth Factor-β1

The role of transforming growth factor (TGF)-β in the infarcted myocardium

Curcumin suppresses transforming growth factor-β1-induced cardiac fibroblast differentiation via inhibition of Smad-2 and p38 MAPK signaling pathways

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