MicroRNA-124 Suppresses the Transactivation of Nuclear Factor of Activated T Cells by Targeting Multiple Genes and Inhibits the Proliferation of Pulmonary Artery Smooth Muscle Cells

Kang, Kang; Peng, Xiao; Zhang, Xiaoying; Wang, Yuna; Zhang, Lishu; Gao, Li; Weng, Tingting; Zhang, Honghao; Ramchandran, Ramaswamy; Raj, J. Usha; Gou, Deming; Liu, Lin

doi:10.1074/jbc.m113.460287

Cited by 116 publications

(98 citation statements)

References 62 publications

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“…The nuclear factor of activated T cells (NFAT) signaling pathway is linked to PASMC proliferation and PAH (55). Kang et al found that miR-124 inhibited NFAT receptor activity and decreased both the dephosphorylation and the nuclear translocation of NFAT (55). Hypoxia downregulated miR-124 in human PASMCs; consistent with the activation of NFAT during this process.…”

Section: Epigeneticsmentioning

confidence: 62%

“…Hypoxia downregulated miR-124 in human PASMCs; consistent with the activation of NFAT during this process. Overexpression of miR-124 not only inhibited human PASMC proliferation, but also maintained its differentiated phenotype by repressing the NFAT pathway (55). It was reported that miR-206 regulates PASMC proliferation and differentiation (56) and that miR-210 has antiapoptotic effects in PASMCs during hypoxia (57).…”

Section: Epigeneticsmentioning

confidence: 99%

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Molecular Mechanisms of Pulmonary Arterial Remodeling

Crosswhite

Sun

2014

Mol Med

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Pulmonary arterial hypertension (PAH) is characterized by a persistent elevation of pulmonary arterial pressure and pulmonary arterial remodeling with unknown etiology. Current therapeutics available for PAH are primarily directed at reducing the pulmonary blood pressure through their effects on the endothelium. It is well accepted that pulmonary arterial remodeling is primarily due to excessive pulmonary arterial smooth muscle cell (PASMC) proliferation that leads to narrowing or occlusion of the pulmonary vessels. Future effective therapeutics will be successful in reversing the vascular remodeling in the pulmonary arteries and arterioles. The purpose of this review is to provide updated information on molecular mechanisms involved in pulmonary arterial remodeling with a focus on growth factors, transcription factors, and epigenetic pathways in PASMC proliferation. In addition, this review will highlight novel therapeutic strategies for potentially reversing PASMC proliferation.

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Section: Epigeneticsmentioning

confidence: 62%

Section: Epigeneticsmentioning

confidence: 99%

Molecular Mechanisms of Pulmonary Arterial Remodeling

Crosswhite

Sun

2014

Mol Med

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“…Kang et al observed that miRNA-124 exerted its antiproliferative and prodifferentiation effects in human PASMC by inhibiting NFATc1 dephosphorylation and nuclear translocation in chronic hypoxia-induced mouse PAH model. 38 By contrast, Chan et al demonstrated that activation of NFATc1 by phenamil may exhibit protective effects in hypoxia-induced SD rat PAH model. 47 The reason of the opposite effect of NFATc1 in PAH between 2 studies is unclear, but may be due to different animal models.…”

Section: Nfatc1 and Nfatc4mentioning

confidence: 99%

“…Therefore, the underlying molecular mechanisms by which NFAT proteins regulate the PASMC phenotype require further investigation. 38 NFATc3 may be involved in the entire hypoxic pulmonary vascular remodeling process, including initial proliferation and subsequent hypertrophy of PASMC. More evidence for NFATc3 involvement in PAH was provided by studies from other animal models.…”

Section: Nfatc3mentioning

confidence: 99%

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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“…Down-regulation of miR-124 in hypoxia-treated PASMC is consistent with the activation of NFAT signaling pathway in hypoxia by targeting NFATc1, CAMTA1 and PTBP1 genes [44]. Fhl-1 is a member of the LIM family and acts as an early key protein in the mechanism of PAH [45].…”

Section: Pahmentioning

confidence: 70%

MicroRNAs and Smooth Muscle Cells Phenotypic Switching in PAH

Wu¹

2014

J Pulm Respir Med

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Smooth muscle cells undergo a switching from contractile phenotype to synthetic phenotype in pulmonary hypertension characterized by excessive proliferation and migration of smooth muscle cells. MicroRNAs are small noncoding RNAs that can negatively regulate gene expression by directly binding with the 3'-UTR of mRNA. Numerous microRNAs have been reported to modulate the smooth muscle cells phenotypic switching and been urged to become possible therapeutic targets for pulmonary hypertension. This review will focus on the roles of microRNAs in regulating smooth muscle cellular phenotypic switching in PAH. MicroRNAs (miRNAs) are a novel class of endogenous, small and non-coding RNAs that function in transcriptional and posttranscriptional regulation of gene expression by directly binding with the 3'-UTR of mRNA [6][7][8]. miRNAs can directly regulate about 30% of the genes in a cell [9], therefore it is not surprising that miRNAs are involved in the regulation of almost all major cellular function, including developmental timing, cell death, cell proliferation [10,11], fat storage [12], haematopoiesis [13][14][15][16][17][18] and patterning of the nervous system [19][20][21][22]. Recent studies have revealed that many non-coding miRNAs can be as novel phenotypic markers and modulators of Vascular Smooth Muscle Cells (VSMCs). These findings display extensive implications for the diagnosis and therapy of a variety of proliferative vascular diseases [23], including PAH. The review will focus on the roles of microRNAs in regulating smooth muscle cellular phenotypic switching in pulmonary hypertension.There are two classic pulmonary hypertension animal models apart induced by monocrotaline (MCT) and hypoxia [24]. In pulmonary hypertension induced by MCT, it usually occurs that endothelial cells damage accompanied with the increasing release of growth factors. PDGF is one of the most common growth factors in PAH and released primarily by vascular endothelial cells and platelets at the sites of vascular injury [25]. Indeed, an increased expression of signaling proteins in the PDGF pathway has been demonstrated in several cardiovascular disorders [26]. Activation of PDGF inhibits smooth muscle cell (SMC)-specific gene expression (SM22α, SM α-actin and calponin) and increases the rate of proliferation and migration, leading to dedifferentiation of VSMCs. Many miRNAs have been demonstrated to play important roles in the stimulation of PDGF with indistinct mechanisms.MiR-15b is shown to be induced by PDGF in pulmonary artery smooth muscle cells and it is critical for the repression of SMC-specific contractile genes [27]. MiR-638 is abundantly expressed in SMCs and markedly down-regulated in the PDGF stimulation. In differentiation medium, miR-638 expression is significantly up-regulated to inhibit SMC proliferation by targeting the orphan nuclear receptor NOR1 [25]. MiR-24 also functions in the process and directly down-regulates Tribbles like protein-3 (Trb3) expression which results in decreased Smad protein levels...

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MicroRNA-124 Suppresses the Transactivation of Nuclear Factor of Activated T Cells by Targeting Multiple Genes and Inhibits the Proliferation of Pulmonary Artery Smooth Muscle Cells

Cited by 116 publications

References 62 publications

Molecular Mechanisms of Pulmonary Arterial Remodeling

Molecular Mechanisms of Pulmonary Arterial Remodeling

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

MicroRNAs and Smooth Muscle Cells Phenotypic Switching in PAH

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