The Role of c‐SKI in Regulation of TGFβ‐Induced Human Cardiac Fibroblast Proliferation and ECM Protein Expression

Wang, Juan; Guo, Liping; Shen, Difei; Xu, Xiao Hui; Wang, Jiaping; Han, Suxia; He, Wen

doi:10.1002/jcb.25935

Cited by 15 publications

(18 citation statements)

References 51 publications

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“…TGF-β induces cellular matrix production by activating MFB during cardiac fibrogenesis; however, transient Ski overexpression in MFB decreases Smad2 phosphorylation, which results in a decrease in type I collagen synthesis and α-SMA levels. 169 , 240 In this case, stable overexpression of Ski promotes cardiac MFB apoptosis. 241 Bone marrow progenitor cell therapy modulates cardiac fibrosis in diabetic hearts by decreasing miR-155 levels, whereas overexpression of miR-155 in cardiac fibroblasts inhibits Ski and SnoN expression.…”

Section: Regulation Of Tgf-β/smad Signaling By Ski and Snonmentioning

confidence: 99%

Transcriptional cofactors Ski and SnoN are major regulators of the TGF-β/Smad signaling pathway in health and disease

Tecalco-Cruz

Ríos-López

Vázquez‐Victorio

et al. 2018

Sig Transduct Target Ther

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The transforming growth factor-β (TGF-β) family plays major pleiotropic roles by regulating many physiological processes in development and tissue homeostasis. The TGF-β signaling pathway outcome relies on the control of the spatial and temporal expression of >500 genes, which depend on the functions of the Smad protein along with those of diverse modulators of this signaling pathway, such as transcriptional factors and cofactors. Ski (Sloan-Kettering Institute) and SnoN (Ski novel) are Smad-interacting proteins that negatively regulate the TGF-β signaling pathway by disrupting the formation of R-Smad/Smad4 complexes, as well as by inhibiting Smad association with the p300/CBP coactivators. The Ski and SnoN transcriptional cofactors recruit diverse corepressors and histone deacetylases to repress gene transcription. The TGF-β/Smad pathway and coregulators Ski and SnoN clearly regulate each other through several positive and negative feedback mechanisms. Thus, these cross-regulatory processes finely modify the TGF-β signaling outcome as they control the magnitude and duration of the TGF-β signals. As a result, any alteration in these regulatory mechanisms may lead to disease development. Therefore, the design of targeted therapies to exert tight control of the levels of negative modulators of the TGF-β pathway, such as Ski and SnoN, is critical to restore cell homeostasis under the specific pathological conditions in which these cofactors are deregulated, such as fibrosis and cancer.

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Section: Regulation Of Tgf-β/smad Signaling By Ski and Snonmentioning

confidence: 99%

Transcriptional cofactors Ski and SnoN are major regulators of the TGF-β/Smad signaling pathway in health and disease

Tecalco-Cruz

Ríos-López

Vázquez‐Victorio

et al. 2018

Sig Transduct Target Ther

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“…[17][18][19] Recently, researchers have focused on the effects of c-Ski in cardiac fibrosis. 13 Experimental studies in animal models revealed that atrial fibrosis plays an important role in the induction and maintenance of AF. 20 Zhang et al found that c-Ski can ameliorate isoproterenol-induced myocardial fibrosis in a rat model and reduce both TGF-β1-induced proliferation of primary rat cardiac fibroblasts and ECM deposition.…”

Section: Discussionmentioning

confidence: 99%

“…10 Cunnington et al demonstrated the antifibrotic properties of c-Ski and its role in the regulation of cardiac myofibroblast phenotype and contractility. 13 Although these studies provided promising evidence in support of the involvement of c-Ski in cardiac fibrosis, mechanistic data on the roles of these small molecules in AF and the associated atrial remodelling in animal models are still lacking. 12 In addition, our previous studies confirmed the repressive effect of c-Ski on TGF-β1-induced human cardiac fibroblast proliferation and ECM protein synthesis.…”

mentioning

confidence: 99%

Effect of c‐Ski on atrial remodelling in a rapid atrial pacing canine model

Wang

Han²,

Han

et al. 2019

J Cellular Molecular Medi

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Atrial fibrosis is an important factor in the initiation and maintenance of atrial fibrillation (AF); therefore, understanding the pathogenesis of atrial fibrosis may reveal promising therapeutic targets for AF. In this study, we successfully established a rapid atrial pacing canine model and found that the inducibility and duration of AF were significantly reduced by the overexpression of c‐Ski, suggesting that this approach may have therapeutic effects. c‐Ski was found to be down‐regulated in the atrial tissues of the rapid atrial pacing canine model. We artificially up‐regulated c‐Ski expression with a c‐Ski–overexpressing adenovirus. Haematoxylin and eosin, Masson's trichrome and picrosirius red staining showed that c‐Ski overexpression alleviated atrial fibrosis. Furthermore, we found that the expression levels of collagen III and α‐SMA were higher in the groups of dogs subjected to right‐atrial pacing, and this increase was attenuated by c‐Ski overexpression. In addition, c‐Ski overexpression decreased the phosphorylation of smad2, smad3 and p38 MAPK (p38α and p38β) as well as the expression of TGF‐β1 in atrial tissues, as shown by a comparison of the right‐atrial pacing + c‐Ski‐overexpression group to the control group with right‐atrial pacing only. These results suggest that c‐Ski overexpression improves atrial remodelling in a rapid atrial pacing canine model by suppressing TGF‐β1–Smad signalling and p38 MAPK activation.

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“…However, no precise mechanism underlying the pathogenic process of cardiomyocyte hypertrophy had been reported. Currently, metalloproteinase and integrin in extracellular matrix are considered to be the major factors related with cardiac remodeling 11. Integrins usually act as mediator and mechanical pressure transmitters between cells and extracellular matrix, activate the integrin signaling pathway, and then affect various cellular functions 12, 13…”

Section: Introductionmentioning

confidence: 99%

“…Currently, metalloproteinase and integrin in extracellular matrix are considered to be the major factors related with cardiac remodeling. 11 Integrins usually act as mediator and mechanical pressure transmitters between cells and extracellular matrix, activate the integrin signaling pathway, and then affect various cellular functions. 12,13 A disintegrin and metalloprotease-22 (ADAM22) is a member of the ADAM family, which is transmembrane and secreted metalloendopeptidases that can regulate cell adhesion, inflammation, and cancer development.…”

mentioning

confidence: 99%

A Disintegrin and Metalloprotease‐22 Attenuates Hypertrophic Remodeling in Mice Through Inhibition of the Protein Kinase B Signaling Pathway

Ren

Yang

et al. 2018

JAHA

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BackgroundSevere cardiac hypertrophy can lead to cardiac remodeling and even heart failure in the end, which is a leading cause of cardiovascular disease–related mortality worldwide. A disintegrin and metalloprotease‐22 (ADAM22), a member of the transmembrane and secreted metalloendopeptidase family, participates in many biological processes, including those in the cardiovascular system. However, there is no explicit information on whether ADAM22 can regulate the process of cardiac hypertrophy; the effects that ADAM22 exerts in cardiac hypertrophy remain elusive.Methods and ResultsWe observed significantly increased ADAM22 expression in failing hearts from patients with dilated cardiomyopathy and hypertrophic cardiomyopathy; the same trend was observed in mice induced by transaortic constriction and in neonatal rat cardiomyocytes treated by angiotensin II. Therefore, we constructed both cardiac‐specific ADAM22 overexpression and knockout mice. At 4 weeks after transaortic constriction, cardiac‐specific ADAM22 knockout, by the CRISPR/Cas9 (clustered regularly interspaced palindromic repeat (CRISPR)–Cas9) system, deteriorated the severity of cardiac hypertrophy in mice, whereas cardiac‐specific ADAM22 overexpression mitigated the degrees of cardiac hypertrophy in mice. Similarly, altered ADAM22 expression modulated the angiotensin II–mediated cardiomyocyte hypertrophy in neonatal rat cardiomyocytes. After screening several signaling pathways, we found ADAM22 played a role in inhibition of protein kinase B (AKT) activation. Under the cardiac‐specific ADAM22 knockout background, AKT activation was enhanced in transaortic constriction–induced mice and angiotensin II–stimulated neonatal rat cardiomyocytes, with a severe degree of cardiac hypertrophy. Treatment of a specific AKT inhibitor attenuated the transaortic constriction–enhanced AKT activation and cardiac hypertrophy in mice.ConclusionsThe findings demonstrated that ADAM22 negatively regulates the AKT activation and the process of cardiac hypertrophy and may provide new insights into the pathobiological features of cardiac hypertrophy.

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The Role of c‐SKI in Regulation of TGFβ‐Induced Human Cardiac Fibroblast Proliferation and ECM Protein Expression

Cited by 15 publications

References 51 publications

Transcriptional cofactors Ski and SnoN are major regulators of the TGF-β/Smad signaling pathway in health and disease

Transcriptional cofactors Ski and SnoN are major regulators of the TGF-β/Smad signaling pathway in health and disease

Effect of c‐Ski on atrial remodelling in a rapid atrial pacing canine model

A Disintegrin and Metalloprotease‐22 Attenuates Hypertrophic Remodeling in Mice Through Inhibition of the Protein Kinase B Signaling Pathway

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