Prostacyclin Analogue Beraprost Inhibits Cardiac Fibroblast Proliferation Depending on Prostacyclin Receptor Activation through a TGF β-Smad Signal Pathway

Chen, Yun; Yang, Shengju; Yao, Wenjuan; Xu, Xiaole; Zhang, Wei

doi:10.1371/journal.pone.0098483

Cited by 36 publications

(29 citation statements)

References 63 publications

(83 reference statements)

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“…Consequently, these Smad proteins represent intracellular therapeutic targets for the manipulation of TGF‐β1‐mediated fibrosis. The inhibition of TGF‐β1‐induced phosphorylation of Smad2 and Smad3 has been demonstrated in models of renal, hepatic, cardiac, and pulmonary fibrosis . Previous studies from our laboratory utilizing RNAi‐mediated knockdown models have shown that TGF‐β1‐mediated Smad2/3 phosphorylation is an essential step for fibroblast transdifferentiation to myofibroblasts .…”

Section: Discussionmentioning

confidence: 96%

Molecular mechanisms of suberoylanilide hydroxamic acid in the inhibition of TGF‐β1‐mediated canine corneal fibrosis

Gronkiewicz

Giuliano

Sharma

et al. 2015

Veterinary Ophthalmology

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Objective To investigate molecular mechanisms mediating anti-fibrotic effect of SAHA in the canine cornea using an in vitro model. We hypothesized that SAHA attenuates corneal fibrosis by modulating Smad-dependent and, to a lesser extent, Smad-independent signaling pathways activated by TGF-β1, as well as matrix metalloproteinase (MMP) activity. Methods Cultured canine corneal fibroblasts (CCF) were incubated in the presence/absence of TGF-β1 (5ng/ml) and SAHA (2.5μM) for 24hrs. Western blot analysis was used to quantify non-phosphorylated and phosphorylated isoforms of Smad2/3, p38 MAP kinase (MAPK), ERK1/2 and JNK1. Real-time PCR and zymography were utilized to quantify MMP1, MMP2, MMP8 and MMP9 mRNA expression and MMP2 and MMP9 protein activity, respectively. Results TGF-β1 treatment caused a significant increase in phospho-Smad2/3 and phospho-p38 MAPK. SAHA treatment reduced TGF-β1-induced phosphorylation of Smad2/3 but not of p38 MAPK. TGF-β1 did not modulate the phosphorylation of ERK1/2 or JNK1. SAHA caused a significant reduction in phospho-ERK1/2 expression regardless of concurrent TGF-β1 treatment. Neither SAHA alone nor in combination with TGF-β1 altered phospho-JNK1 expression. TGF-β1 significantly increased MMP1 and MMP9 mRNA expression but did not alter MMP2 mRNA. SAHA treatment attenuated TGF-β1-induced MMP9 mRNA expression while significantly enhancing TGF-β1-induced MMP1 mRNA expression. Zymography detected reduced expression of MMP2 and MMP9 proteins in untreated control CCF. TGF-β1 treatment did not alter their expression but SAHA treatment +/−TGF-β1 significantly increased MMP2 and MMP9 protein expression. Conclusions The corneal anti-fibrotic effects of SAHA involve multiple mechanisms including modulation of canonical and non-canonical components of TGF-β1 intracellular signaling and MMP activity.

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Section: Discussionmentioning

confidence: 96%

Molecular mechanisms of suberoylanilide hydroxamic acid in the inhibition of TGF‐β1‐mediated canine corneal fibrosis

Gronkiewicz

Giuliano

Sharma

et al. 2015

Veterinary Ophthalmology

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“…However, the vasculature is not the only site of IP expression in the myocardium. Although most of the IP mRNA in the mouse myocardium was found in noncardiomyocyte cells [6], this receptor was also reported to be expressed in such other cells as cardiac fibroblasts [2]. More detailed studies on isolated coronary arteries are needed to assess the actual expression levels of the IP in the vasculature.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of cyclooxygenase-2 causes a decrease in coronary flow in diabetic mice. The possible role of PGE2 and dysfunctional vasodilation mediated by prostacyclin receptor

et al. 2015

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Several lines of evidence suggest that cyclooxygenase-2 (COX-2) activity can have a beneficial role in the maintenance of vascular tone of the blood vessels in diabetes. Specifically, the increased production of prostacyclin (PGI2) and prostaglandin E2 (PGE2), mediated by COX-2, has been suggested to compensate for decreased synthesis of nitric oxide (NO). The study investigates whether inhibition of COX-2 may reduce the coronary flow in diabetic animals and may also lead to decreased synthesis of prostaglandins. Mice aged 18-20 weeks were used for the study: those with leptin receptor deficiency (db/db) served as a model of diabetes while heterozygous (db/+) mice served as controls. Coronary flow was measured by the Langendorff method, and prostaglandin synthesis by myocardia was assayed in heart perfusates. COX-2 inhibition was found to reduce basal coronary flow in db/db mice but had no effect in db/+ mice. Secretion of PGE2 was found to be higher in db/db mice, while prostacyclin synthesis did not differ. COX-2 inhibition decreased production of both prostaglandins to similar levels in both groups. The use of ONO-1301, a specific agonist for the prostacyclin receptor revealed that vasodilating responses mediated by the receptor were impaired in db/db mice. The expression levels of the receptor in cardiac tissue did not differ between the groups. It is concluded that the increased COX-2 contribution to vasodilation in diabetic animals appears to be partially a result of increased COX-2-dependent synthesis of PGE2 and also may be caused by impaired vasodilation mediated by the prostacyclin receptor.

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“…In particular, activation of EP 4 and IP by synthetic analogs of prostaglandin E2 (PGE2) and prostacyclin, respectively, has been shown to inhibit TGFβ1-mediated synthesis of collagen type 1 and type 3 [65,66], and Ang-II-induced proliferation of rat cardiac fibroblasts [67]. These effects were shown to require cAMP production [65,67].…”

Section: Additional Gs-coupled Gpcr Regulating Fibrotic Responsesmentioning

confidence: 99%

The Role of Cyclic AMP Signaling in Cardiac Fibrosis

Delaunay

Osman

Kaiser

et al. 2019

Cells

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Myocardial stress and injury invariably promote remodeling of the cardiac tissue, which is associated with cardiomyocyte death and development of fibrosis. The fibrotic process is initially triggered by the differentiation of resident cardiac fibroblasts into myofibroblasts. These activated fibroblasts display increased proliferative capacity and secrete large amounts of extracellular matrix. Uncontrolled myofibroblast activation can thus promote heart stiffness, cardiac dysfunction, arrhythmias, and progression to heart failure. Despite the well-established role of myofibroblasts in mediating cardiac disease, our current knowledge on how signaling pathways promoting fibrosis are regulated and coordinated in this cell type is largely incomplete. In this respect, cyclic adenosine monophosphate (cAMP) signaling acts as a major modulator of fibrotic responses activated in fibroblasts of injured or stressed hearts. In particular, accumulating evidence now suggests that upstream cAMP modulators including G protein-coupled receptors, adenylyl cyclases (ACs), and phosphodiesterases (PDEs); downstream cAMP effectors such as protein kinase A (PKA) and the guanine nucleotide exchange factor Epac; and cAMP signaling organizers such as A-kinase anchoring proteins (AKAPs) modulate a variety of fundamental cellular processes involved in myocardial fibrosis including myofibroblast differentiation, proliferation, collagen secretion, and invasiveness. The current review will discuss recent advances highlighting the role of cAMP and AKAP-mediated signaling in regulating pathophysiological responses controlling cardiac fibrosis.

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Prostacyclin Analogue Beraprost Inhibits Cardiac Fibroblast Proliferation Depending on Prostacyclin Receptor Activation through a TGF β-Smad Signal Pathway

Cited by 36 publications

References 63 publications

Molecular mechanisms of suberoylanilide hydroxamic acid in the inhibition of TGF‐β1‐mediated canine corneal fibrosis

Molecular mechanisms of suberoylanilide hydroxamic acid in the inhibition of TGF‐β1‐mediated canine corneal fibrosis

Inhibition of cyclooxygenase-2 causes a decrease in coronary flow in diabetic mice. The possible role of PGE2 and dysfunctional vasodilation mediated by prostacyclin receptor

The Role of Cyclic AMP Signaling in Cardiac Fibrosis

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