Inhibition of phosphodiesterase-5 suppresses calcineurin/NFAT- mediated TRPC6 expression in pulmonary artery smooth muscle cells

Li, Shaojun; Pan, Yilin; Rui, Ke; Xie, Xinming; Zhai, Cui; Shi, Wenhua; Wang, Jian; Yan, Xin; Chai, Limin; Wang, Qingting; Zhang, Qianqian; Su, Xiaofan; Yang, Lan; Gao, Li; Li, Manxiang

doi:10.1038/s41598-017-06350-5

Cited by 13 publications

(13 citation statements)

References 46 publications

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“…calcineurin is a calcium-activated protein phosphatase that has been implicated in various inflammatory diseases (25). activated calcineurin dephosphorylates the nuclear factor of activated T cells (nFaT), which, in turn, modulates the transcription of target genes associated with cellular proliferation, differentiation, inflammation and angiogenesis (14). The nFaT protein family consists of the following five members: NFATc1, nFaTc2, nFaTc3, nFaTc4 and nFaT5 [tonicity-responsive enhancer-binding protein (ToneBP)] (26).…”

Section: Discussionmentioning

confidence: 99%

“…an increase in the levels of intracellular ca 2+ activates calcineurin. activated calcineurin dephosphorylates the nuclear factor of activated T cells (nFaT), which in turn modulates the transcription of target genes (14). in recent years, various inflammatory cytokines and adhesion molecules have been identified as NFAT regulatory targets (15).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of calcineurin/NFATc4 signaling attenuates ventilator‑induced lung injury

Fang

Liu

et al. 2019

Mol Med Report

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Ventilator-induced lung injury (Vili) is a life-threatening condition caused by the inappropriate use of mechanical ventilation (MV). However, the precise molecular mechanism inducing the development of Vili remains to be elucidated. in the present study, it was revealed that the calcineurin/nFaTc4 signaling pathway mediates the expression of adhesion molecules and proinflammatory cytokines essential for the development of Vili. The present results revealed that a high tidal volume ventilation (HV) caused lung inflammation and edema in the alveolar walls and the infiltration of inflammatory cells. The calcineurin activity and protein expression in the lungs were increased in animals with Vili, and nFaTc4 translocated into the nucleus following calcineurin activation. Furthermore, the translocation of nFaTc4 and lung injury were prevented by a calcineurin inhibitor (csa). Thus, the present results highlighted the critical role of the calcineurin/nFaTc4 signaling pathway in Vili and suggest that this pathway coincides with the release of icaM-1, VcaM-1, TnF-α and il-1β.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of calcineurin/NFATc4 signaling attenuates ventilator‑induced lung injury

Fang

Liu

et al. 2019

Mol Med Report

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“…Primary PASMC were obtained from pulmonary arteries of Sprague-Dawley male rats (70-80 g) according to the method reported previously. [21][22][23][24] All animal care and experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals of Xi'an Jiaotong University Animal Experiment Center. All protocols used in this study were approved by the Laboratory Animal Care Committee of Xi'an Jiaotong University.…”

Section: Cell Preparation and Culturementioning

confidence: 99%

SphK1/S1P mediates TGF‐β1‐induced proliferation of pulmonary artery smooth muscle cells and its potential mechanisms

Wang

Feng

et al. 2018

Pulm. circ.

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The upregulation of Sphingosine kinase 1 (SphK1) expression and accompanied sphingosine-1-phosphate (S1P) production have been reported to contribute to the proliferation of pulmonary artery smooth muscle cells (PASMC) and pulmonary arterial remodeling. However, the molecular mechanisms of SphK1/S1P upregulation in PASMC and the specific mechanisms of how SphK1/S1P pathway promotes PASMC proliferation remain largely unclear. This study aims to address these issues. Here, we demonstrated that TGF-β1 significantly upregulated SphK1 expression and S1P production by promoting the phosphorylation of Smad2/3 in PASMC. Further study indicated that SphK1/S1P pathway mediated TGF-β1-induced Notch3 activation in PASMC. In addition, we showed that TGF-β1 significantly induced proliferation of PASMC, while pre-inhibition of Smad2/3 phosphorylation with SB431542 or silencing SphK1 using small interfering RNA in advance, or pre-blocking Notch3 pathway with N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), attenuated TGF-β1-induced PASMC proliferation. Taken together, our study indicates that Smad2/3/SphK1/S1P/Notch3 pathway mediates TGF-β1-induced PASMC proliferation and suggests this pathway as a potential therapeutic target in the prevention and treatment of pulmonary hypertension.

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“…NFATc4, a member of nuclear factor of activated T cells (NFAT) transcription factor family, has been well-documented for its involvement in several diseases including cardiac hypertrophy, by regulating various target genes (Horsley and Pavlath, 2002; Li et al, 2016a, 2017; Zhang and Storey, 2016; Wang et al, 2017; Sharma et al, 2018). Similar as other NFAT subtypes, NFATc4 is dephosphorylated and activated by CaN (van Middendorp et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Similar as other NFAT subtypes, NFATc4 is dephosphorylated and activated by CaN (van Middendorp et al, 2017). After dephosphorylation, NFATc4 is transported from the cytoplasm to the nucleus and binds to target DNA to regulate the expression of hypertrophic genes, in particular the hypertrophic marker BNP (Molkentin et al, 1998; Crabtree, 1999; Liu et al, 2015; Li et al, 2016a, 2017). In addition, NFATc4 interacts with other hypertrophic signaling pathways, such as GATA-4, MAPK, GSK3, p38, and JNK (Coleman et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

SIRT6 Suppresses NFATc4 Expression and Activation in Cardiomyocyte Hypertrophy

Zhang

Guo

et al. 2019

Front. Pharmacol.

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NFATc4, a member from the Nuclear Factor of Activated T cells (NFATs) transcription factor family, plays a pivotal role in the development of cardiac hypertrophy. NFATc4 is dephosphorylated by calcineurin and translocated from the cytoplasm to the nucleus to regulate the expression of hypertrophic genes, like brain natriuretic polypeptide (BNP). The present study identified SIRT6, an important subtype of NAD+ dependent class III histone deacetylase, to be a negative regulator of NFATc4 in cardiomyocyte hypertrophy. In phenylephrine (PE)-induced hypertrophic cardiomyocyte model, overexpression of SIRT6 by adenovirus infection or by plasmid transfection repressed the protein and mRNA expressions of NFATc4, elevated its phosphorylation level, prevented its nuclear accumulation, subsequently suppressed its transcriptional activity and downregulated its target gene BNP. By contrast, mutant of SIRT6 without deacetylase activity (H133Y) did not demonstrate these effects, suggesting that the inhibitory effect of SIRT6 on NFATc4 was dependent on its deacetylase activity. Moreover, the effect of SIRT6 overexpression on repressing BNP expression was reversed by NFATc4 replenishment, whereas the effect of SIRT6 deficiency on upregulating BNP was recovered by NFATc4 silencing. Mechanistically, interactions between SIRT6 and NFATc4 might possibly facilitate the deacetylation of NFATc4 by SIRT6, thereby preventing the activation of NFATc4. In conclusion, the present study reveals that SIRT6 suppresses the expression and activation of NFATc4. These findings provide more evidences of the anti-hypertrophic effect of SIRT6 and suggest SIRT6 as a potential therapeutic target for cardiac hypertrophy.

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Inhibition of phosphodiesterase-5 suppresses calcineurin/NFAT- mediated TRPC6 expression in pulmonary artery smooth muscle cells

Cited by 13 publications

References 46 publications

Inhibition of calcineurin/NFATc4 signaling attenuates ventilator‑induced lung injury

Inhibition of calcineurin/NFATc4 signaling attenuates ventilator‑induced lung injury

SphK1/S1P mediates TGF‐β1‐induced proliferation of pulmonary artery smooth muscle cells and its potential mechanisms

SIRT6 Suppresses NFATc4 Expression and Activation in Cardiomyocyte Hypertrophy

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