Sildenafil inhibits calcineurin/NFATc2-mediated cyclin A expression in pulmonary artery smooth muscle cells

Li, Manxiang; Liu, Yuan; Sun, Xuegang; Li, Zongfang; Liu, Yun; Fang, Ping; He, Ping; Shi, Hongyang; Xie, Mei; Wang, Xiaochuang; Zhang, Dexin; Zhang, Yonghong; Zhou, Ming; Xu, Jing; Lu, Jiamei; Xie, Xinming

doi:10.1016/j.lfs.2011.07.023

Cited by 14 publications

(15 citation statements)

References 34 publications

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“…Bonnet et al (23) demonstrated that in PAH, including scleroderma-associated PAH and idiopathic PAH (IPAH), NFATc2 is upregulate and activated in some circulating inflammatory cells. A recent study found that following treatment with 5-HT, calcineurin and NFAT pathway activation occurred in PASMCs, which was related to dosage (24). In addition, following treatment with sidenafil, an inhibitor of PDE5, the serotonin-induced activation of calcineurin/NFATc2 signaling pathway was suppressed, which suggested that one of the major targets of sildenafil was the calcineurin/NFAT cascade in the pulmonary system (24).…”

Section: Discussionmentioning

confidence: 99%

“…A recent study found that following treatment with 5-HT, calcineurin and NFAT pathway activation occurred in PASMCs, which was related to dosage (24). In addition, following treatment with sidenafil, an inhibitor of PDE5, the serotonin-induced activation of calcineurin/NFATc2 signaling pathway was suppressed, which suggested that one of the major targets of sildenafil was the calcineurin/NFAT cascade in the pulmonary system (24). In the present study, the expression of NFAT-1 was markedly increased in the MCT group, which was inhibited by PCPA in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

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The protective effects of PCPA against monocrotaline-induced pulmonary arterial hypertension are mediated through the downregulation of NFAT-1 and NF-κB

Bai

Wang

et al. 2017

International Journal of Molecular Medicine

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Inflammation and remodeling play a role in the pathogenesis of pulmonary arterial hypertension (PAH). Nuclear factor-κB (NF-κB) and nuclear factor of activated T cells-1 (NFAT-1) participate in inflammation and remodeling in a number of diseases. As a tryptophan hydroxylase inhibitor, 4-chloro-DL-phenylalanine (PCPA) had been reported to exert anti-inflammatory and remodeling effects. Therefore, we hypothesized that PCPA may attenuate monocrotaline (MCT)-induced PAH through the NFAT-1 and NF-κB signaling pathways. In order to confirm our hypothesis, we divided 68 Sprague-Dawley male rats into 4 groups as follows: the control, MCT, MCT + P1 and MCT + P2 groups. MCT was administered at a dose of 60 mg/kg once via intraperitoneal injection. PCPA was administered via intraperitoneal injection at a dose of 50 or 100 mg/kg once daily for 21 consecutive days. We then measured the hemodynamic index and morphological analysis was carried out on the lung tissues. Western blot analysis and immunohistochemistry were used to examine the levels of NFAT-1 and NF-κB p-65. The expression levels of phosphorylated inhibitor of NF-κB kinase (p-IKK), IKK, phosphorylated extracellular signal-regulated kinase (p-ERK), ERK, intercellular adhesion molecule-1 (ICAM-1) and interleukin-6 (IL-6) were examined by western blot analysis. MCT was found to significantly induce PAH, with inflammation and remodeling of the lung tissues. This was associatd with an increased expression of NFAT-1, p-IKK, p-ERK and nuclear p65. PCPA significantly attenuated MCT-induced inflammation and arterial remodeling, and decreased the expression of NFAT-1, as well as that of relevant proteins of the NF-κB signaling pathway. The above-mentioned findings suggest that the inhibitory effects of PCPA on MCT-induced inflammation and arterial remodeling are related to the downregulation of the NFAT-1 and NF-κB signaling pathways in rats with PAH.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The protective effects of PCPA against monocrotaline-induced pulmonary arterial hypertension are mediated through the downregulation of NFAT-1 and NF-κB

Bai

Wang

et al. 2017

International Journal of Molecular Medicine

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“…In vitro, several studies reported increased activation of NFATc2 in cultured PASMC in response to 5-HT, endothelin-1(ET-1) and PDGF, which has been implicated in pulmonary vascular remodeling. 16,17 NFATc2 induces PASMC proliferation and resistance to apoptosis within the remodeling PA wall by reducing the expression of Kv1.5 and upregulation of anti-apoptotic protein Bcl-2. 14,18 Kv1.5 has been suggested to regulate the resting plasma membrane potential in PASMC.…”

Section: Nfatc2mentioning

confidence: 99%

“…20 Additionally, as the downstream of calcineurin, NFATc2 upregulates cyclin A expression and CDK2 activation to promote primary cultured PASMC cell cycle and proliferation. 16 VIVIT or CsA induces apoptosis by inhibiting NFATc2 nuclear translocation and subsequent up regulation of Kv1.5 expression and down regulation of Bcl-2 and decrease of [Ca 2C ], [K C ]. 14 Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates the expression of NFATc2 and subsequent proliferation of PASMC.…”

Section: Nfatc2mentioning

confidence: 99%

“…59 Some compounds and drugs, including plumbagin, dichloroaletate and sildenafil have good effects in various models of PAH by inhibiting NFAT gene family. 15,16,60 In clinic, efficacy and safety of endothelin-receptor antagonist has been confirmed in PAH patients. [61][62][63][64] Because ET-1 (upregulated in PAH) activates NFATc1, which in turn increases bcl ¡ 2 expression, contributing to the prosurvival and antiapoptotic effects of ET-1, 65 endothelin-receptor antagonist might also inhibit NFAT activation.…”

Section: Targeting the Nfat Pathway For Pah Therapymentioning

confidence: 99%

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The role of nuclear factor of activated T cells in pulmonary arterial hypertension

et al. 2017

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Nuclear factor of activated T cells (NFAT) was first identified as a transcription factor about 3 decades ago and was not well studied until the development of immunosuppressant. Numerous studies confirm that calcineurin/NFAT signaling is very important in the development of vasculature and cardiovascular system during embryogenesis and is involved in the development of vascular diseases such as hypertension, atherosclerosis and restenosis. Recent studies demonstrated that NFAT proteins also regulate immune response and vascular cells in the pulmonary microenvironment. In this review, we will discuss how different NFAT isoforms contribute to pulmonary vascular remodeling and potential new therapeutic targets for treating pulmonary arterial hypertension.

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The many faces of calmodulin in cell proliferation, programmed cell death, autophagy, and cancer

Berchtold

Villalobo

2014

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

293

261

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Calmodulin (CaM) is a ubiquitous Ca(2+) receptor protein mediating a large number of signaling processes in all eukaryotic cells. CaM plays a central role in regulating a myriad of cellular functions via interaction with multiple target proteins. This review focuses on the action of CaM and CaM-dependent signaling systems in the control of vertebrate cell proliferation, programmed cell death and autophagy. The significance of CaM and interconnected CaM-regulated systems for the physiology of cancer cells including tumor stem cells, and processes required for tumor progression such as growth, tumor-associated angiogenesis and metastasis are highlighted. Furthermore, the potential targeting of CaM-dependent signaling processes for therapeutic use is discussed.

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Sildenafil inhibits calcineurin/NFATc2-mediated cyclin A expression in pulmonary artery smooth muscle cells

Cited by 14 publications

References 34 publications

The protective effects of PCPA against monocrotaline-induced pulmonary arterial hypertension are mediated through the downregulation of NFAT-1 and NF-κB

The protective effects of PCPA against monocrotaline-induced pulmonary arterial hypertension are mediated through the downregulation of NFAT-1 and NF-κB

The role of nuclear factor of activated T cells in pulmonary arterial hypertension

The many faces of calmodulin in cell proliferation, programmed cell death, autophagy, and cancer

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