Decreased Smad 7 expression contributes to cardiac fibrosis in the infarcted rat heart

Wang, Baiqiu; Hao, J. M.; Jones, Stephen C.; Yee, May Sann; Roth, Julie C.; Dixon, Ian M.C.

doi:10.1152/ajpheart.00266.2001

Cited by 138 publications

(104 citation statements)

References 46 publications

(65 reference statements)

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“…Scar formation is considered complete by 3 weeks post MI [46], however, our findings suggest that the scar is not quiescent even at 8 weeks post MI, as indicated by PLD2 activity in the scar tissue. This assumption is also borne out and supported by other recent findings of augmented smad proteinmediated signaling in fibroblasts and myofibroblasts [47,48] as well as increases in the mRNA levels of Giα2 and β-myosin heavy chain in infarct scar [49]. Therefore, it is conceivable that the mechanisms that are activated during the wound healing of the infarct may not be terminated within the defined period of infarct healing and therefore it is suggested that PLD2-mediated signaling may also be involved in the ongoing remodeling of scar morphology.…”

Section: Discussionsupporting

confidence: 72%

Expression of phospholipase D isozymes in scar and viable tissue in congestive heart failure due to myocardial infarction

Dent

Singal

Dhalla

et al. 2004

J Cellular Molecular Medi

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The phospholipase D (PLD) associated with the cardiac sarcolemmal (SL) membrane hydrolyses phosphatidylcholine to produce phosphatidic acid, an important phospholipid signaling molecule known to influence cardiac function. The present study was undertaken to examine PLD isozyme mRNA expression, protein contents and activities in congestive heart failure (CHF) subsequent to myocardial infarction (MI). MI was induced in rats by occlusion of the left anterior descending coronary artery. At 8 weeks after the surgical procedure, hemodynamic assessment revealed that these experimental rats were at a moderate stage of CHF. Semi‐quantitative reverse transcriptase‐polymerase chain reaction revealed that PLD1 and PLD2 mRNA amounts were unchanged in viable left ventricular (LV) tissue of the failing heart. Furthermore, this technique demonstrated the presence of PLD1 and PLD2 mRNA in the scar tissue. While SL PLD1 and PLD2 protein contents were elevated in the viable LV tissue of the failing heart, SL PLD1 activity was significantly decreased, whereas SL PLD2 activity was significantly increased. On the other hand, although PLD1 protein was undetectable, PLD2 protein and activity were detected in the scar tissue. Our findings suggest that differential changes in PLD isozymes may contribute to the pathophysiology of CHF and may also be involved in the processes of scar remodeling.

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Section: Discussionsupporting

confidence: 72%

Expression of phospholipase D isozymes in scar and viable tissue in congestive heart failure due to myocardial infarction

Dent

Singal

Dhalla

et al. 2004

J Cellular Molecular Medi

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“…Moreover, Smad7 expression is induced by TGF-β1 and may act via an autoregulatory negative feedback loop (24). We found no significant change in Smad7 gene expression after TGF-β1 stimulation for 24 h, which was consistent with previous reports (15,16).…”

Section: Discussionsupporting

confidence: 93%

Smad2 and Smad3 as mediators of the response of adventitial fibroblasts induced by transforming growth factor β1

et al. 2011

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Abstract. Transforming growth factor β1 (TGF-β1) is a known pleiotropic growth factor in cell proliferation, migration and phenotypic transition. Fibroblasts are considered the most reactive in the vascular wall. We aimed to explore the effect and mechanism of TGF-β1 on aortal adventitial fibroblasts (AFs) induced by TGF-β1. aFs were cultured in vitro by tissue explants. after stimulation by TGF-β1 and treatment with small interfering rna (sirna)-Smad2 and sirna-Smad3, MTT and the transwell chamber techniques were used for assessing aF proliferation and migration. The expression of phospho (pho)-Smad2, pho-Smad3, Smad7, α-smooth muscle actin (SMa) and collagen i and iii were evaluated by Western blot analysis and real-time rT-Pcr. after stimulation by TGF-β1 for 24 h, the proliferation and migration of treated aFs were higher compared to those of untreated aFs, as was the expression of Smad2, Smad3, phoSmad2, pho-Smad3, SMa and collagen i and iii (P<0.05), but not Smad7 (P>0.05). Knockdown of Smad2 and Smad3 inhibited proliferation and migration of aFs and downregulated the expression of SMa and collagen i and iii (P<0.05). TGF-β1 plays a key role in remodeling processes by contributing to the proliferation, migration and phenotypic modulation of aFs and collagen composition. The mechanism may be related to both the Smad2 and Smad3 signaling pathways.

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“…Activation of resident cardiac fibroblasts into hypersynthetic/secretory myofibroblasts is now generally regarded as the seminal event in the upregulation and enhanced deposition of fibrillar collagens and ECM, which in acute phases assists in cardiac wound healing but in chronic phases ultimately culminates in cardiac dysfunction due to global stiffening of the noninfarcted myocardium remote to the infarct scar (8,34,40,42,43,45). Traditional TGF␤ 1 /Smad signaling has been described as a key regulator of the fibrotic response in the post-MI heart (44).…”

Section: Discussionmentioning

confidence: 99%

TGFβ₁regulates Scleraxis expression in primary cardiac myofibroblasts by a Smad-independent mechanism

Zeglinski

Roché

Hnatowich

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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In cardiac wound healing following myocardial infarction (MI), relatively inactive resident cardiac fibroblasts phenoconvert to hypersynthetic/secretory myofibroblasts that produce large quantities of extracellular matrix (ECM) and fibrillar collagen proteins. Our laboratory and others have identified TGF␤ 1 as being a persistent stimulus in the chronic and inappropriate wound healing phase that is marked by hypertrophic scarring and eventual stiffening of the entire myocardium, ultimately leading to the pathogenesis of heart failure following MI. Ski is a potent negative regulator of TGF␤/Smad signaling with known antifibrotic effects. Conversely, Scleraxis is a potent profibrotic basic helix-loop-helix transcription factor that stimulates fibrillar collagen expression. We hypothesize that TGF␤ 1 induces Scleraxis expression by a novel Smad-independent pathway. Our data support the hypothesis that Scleraxis expression is induced by TGF␤ 1 through a Smad-independent pathway in the cardiac myofibroblast. Specifically, we demonstrate that TGF␤ 1 stimulates p42/44 (Erk1/2) kinases, which leads to increased Scleraxis expression. Inhibition of MEK1/2 using U0126 led to a sequential temporal reduction of phosphop42/44 and subsequent Scleraxis expression. We also found that adenoviral Ski expression in primary myofibroblasts caused a significant repression of endogenous Scleraxis expression at both the mRNA and protein levels. Thus we have identified a novel TGF␤ 1-driven, Smad-independent, signaling cascade that may play an important role in regulating the fibrotic response in activated cardiac myofibroblasts following cardiac injury.

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Decreased Smad 7 expression contributes to cardiac fibrosis in the infarcted rat heart

Cited by 138 publications

References 46 publications

Expression of phospholipase D isozymes in scar and viable tissue in congestive heart failure due to myocardial infarction

Expression of phospholipase D isozymes in scar and viable tissue in congestive heart failure due to myocardial infarction

Smad2 and Smad3 as mediators of the response of adventitial fibroblasts induced by transforming growth factor β1

TGFβ₁regulates Scleraxis expression in primary cardiac myofibroblasts by a Smad-independent mechanism

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Decreased Smad 7 expression contributes to cardiac fibrosis in the infarcted rat heart

Cited by 138 publications

References 46 publications

Expression of phospholipase D isozymes in scar and viable tissue in congestive heart failure due to myocardial infarction

Expression of phospholipase D isozymes in scar and viable tissue in congestive heart failure due to myocardial infarction

Smad2 and Smad3 as mediators of the response of adventitial fibroblasts induced by transforming growth factor β1

TGFβ1regulates Scleraxis expression in primary cardiac myofibroblasts by a Smad-independent mechanism

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TGFβ₁regulates Scleraxis expression in primary cardiac myofibroblasts by a Smad-independent mechanism