Role of Protein Transamidation in Serotonin-Induced Proliferation and Migration of Pulmonary Artery Smooth Muscle Cells

Liu, Yinglin; Lin, Wei; Laskin, Debra L.; Fanburg, Barry L.

doi:10.1165/rcmb.2010-0078oc

Cited by 61 publications

(61 citation statements)

References 48 publications

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“…Serotonylated FN also was elevated in lung tissue and sera of experimental rodent models of PH. These observations, coupled with our previous studies (25) and those of other investigators demonstrating enhanced cellular uptake of 5-HT associated with PH, are consistent with a process of intracellular FN transamidation by the 5-HT and subsequent release of the s-FN into the intercellular space and serum. However, it is also possible that FN in serum may be directly transamidated by 5-HT.…”

Section: Discussionsupporting

confidence: 92%

“…Furthermore, the results are consistent with a hypothesis that exposure to hypoxia stimulates this transport process (17). Serotonylation of FN and other proteins is dependent on 5-HT transport and results in SMC proliferation and migration (25) and enhanced vascular contractility (32) that accompany PH. Whether or not TGase activity is elevated in the process is unknown.…”

Section: Discussionsupporting

confidence: 88%

“…Guilluy et al (10) reported an elevation of serotonylated Rho A and Rho kinase activation in circulating platelets of humans with PH and lungs of 5-HT transporter overexpressing mice. Our own studies showed a role for protein transamidation in serotonin-induced proliferation and migration of pulmonary artery SMCs and suggested that FN is a major cellular protein that participates in serotonylation (25). In cell culture the s-FN is released into extracellular medium.…”

Section: Discussionmentioning

confidence: 91%

“…New insight regarding the possible mechanism by which intracellular 5-HT might exert an intracellular effect comes from our in vitro studies with SMCs showing that 5-HT serotonylates (transaminates) intracellular proteins through the enzyme transglutaminase (TGase) (25). In this study one protein substrate that is highly transaminated by 5-HT is fibronectin (FN).…”

mentioning

confidence: 95%

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Serotonylated fibronectin is elevated in pulmonary hypertension

Lin

Warburton

Preston

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Serotonin (5-HT) and fibronectin (FN) have been associated with pulmonary hypertension (PH). We previously reported that FN is posttranslationally modified by tissue transglutaminase (TGase) to form serotonylated FN (s-FN) in pulmonary artery smooth muscle cells and that serotonylation stimulates their proliferation and migration, hallmarks of PH. We hypothesized that s-FN and its binding to TGase are elevated in human and experimental PH. To assess this hypothesis, FN isolation and electrophoretic, immunoblotting, and densitometric techniques were used. Mean ratio of serum s-FN to total FN level (s-FN/FN) was elevated in 19 consecutive pulmonary arterial hypertension (PAH) patients compared with 25 controls (0.3 Ϯ 0.18 vs. 0.05 Ϯ 0.07, P Ͻ 0.001). s-FN/FN also was increased in lungs of mice and rats with hypoxiainduced PH and in rats with monocrotaline-induced PH. In mice, the increase was detected at 1 wk of hypoxia, preceding the development of PH. Hypoxic rats had elevated serum s-FN/FN. Enhanced binding of TGase to its substrate FN occurred in serum from patients with PAH (mean 0.50 Ϯ 0.51 vs. 0.063 Ϯ 0.11, P ϭ 0.002) and s-FN/FN and TGase-bound FN were highly correlated (R 2 ϭ 0.77). TGasebound FN also was increased in experimental PH. We conclude that increased serotonylation of FN occurs in human and experimental PH and may provide a biomarker for the disease.serotonin; transglutaminase; transglutamidation; hypoxia-and monocrotaline-induced pulmonary hypertension STRONG LINES OF EVIDENCE FROM human and experimental animal models support a role for serotonin (5-HT) and the serotonin transporter (SERT) in the pathogenesis of pulmonary hypertension (PH). Herve et al. (11,12) first identified elevation of plasma 5-HT and reduced platelet 5-HT in association with pulmonary arterial hypertension (PAH) in patients with familial platelet storage disease. About this time it also became recognized that PH is associated with appetite-suppressing derivatives of fenfluramine (e.g., Ref. 1), which along with 5-HT is a substrate for the 5-HT transporter (SERT) (19,30). In the mid-1980s our laboratory reported that exposure of endothelial and smooth muscle cells (SMCs) to hypoxia enhanced cellular transcription of SERT and that this was related to increased cellular glycolysis (17,18). This observation fitted well with known hypoxia-induced PH, later reports of elevated plasma 5-HT in mice developing PH after hypoxic exposure (3) and elevated plasma levels of 5-HT in humans with the idiopathic form of PAH (15). Eddahibi and associates (6) carried these observations further with studies on transgenic mice in which SERT knockout animals failed to develop hypoxia-induced PH and animals selectively overexpressing vascular SERT with a SM22-targeted promoter spontaneously developed PH (9). Furthermore, these investigators reported elevated expression of SERT in cultured pulmonary artery SMCs from patients with PH. A promoter polymorphism in SERT has been described in humans, and the LL genotype has been associated with higher...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 95%

See 2 more Smart Citations

Serotonylated fibronectin is elevated in pulmonary hypertension

Lin

Warburton

Preston

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Indeed, several growth factors and neurotransmitters, such as platelet-derived growth factor (PDGF)-BB (4,5), epidermal growth factor (EGF) (6), serotonin (7), and endothelin-1 (8), have been shown to induce PASMC proliferation and promote the development and progression of PAH. Serotonin (also known as 5-hydroxytryptamine ) is one of the most potent, naturally occurring vasoconstrictors in pulmonary artery remodeling and pulmonary hypertension (7,9,10). Indeed, through the 5-HT transporter (5-HTT) and 5-HT receptors, 5-HT has been shown to trigger activation of PDGF receptorb and mitogen-activated protein kinase (MAPK), thus increasing proliferation of PASMCs (11,12).…”

mentioning

confidence: 99%

Nur77 Suppresses Pulmonary Artery Smooth Muscle Cell Proliferation through Inhibition of the STAT3/Pim-1/NFAT Pathway

Liu

Zhang

et al. 2014

Am J Respir Cell Mol Biol

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The orphan nuclear receptor 4A (NR4A) family plays critical roles in the regulation of cell proliferation, differentiation, and survival in the cardiovascular system. However, the molecular mechanisms underlying the regulation of NR4A receptor expression and its role in pulmonary artery smooth muscle cell (PASMC) function remain unclear. Here, we investigated whether the NR4A family regulates PASMC proliferation, and if so, which mechanisms are involved. By using quantitative real-time RT-PCR, we showed that the orphan nuclear receptor Nur77 was the most abundant member of NR4A family expressed in rat PASMCs, as compared with the two other members, NOR-1 and Nurr1. In rat PASMCs, expression of Nur77 was robustly induced in response to several pathologic stimuli of pulmonary arterial hypertension (PAH), such as hypoxia, 5-hydroxytryptamine (5-HT), platelet-derived growth factor, and endothelin-1. Importantly, Nur77 was also significantly increased in lungs of rats with monocrotaline-induced PAH. Furthermore, we demonstrated that 5-HT markedly up-regulated Nur77 expression through the mitogen-activated protein kinases/extracellular signal-regulated kinase 1/2 pathway. Overexpression of Nur77 inhibited 5-HT-induced PASMC proliferation, as well as the expression of cyclin D1 and proliferating cell nuclear antigen. Mechanistically, we demonstrated that Nur77 specifically interacts with signal transducer and activator of transcription 3, thus inhibiting its phosphorylation and expression of its target genes, such as Pim-1, nuclear factor of activated T cells c2, and survivin in PASMCs. These results indicate that Nur77 is a novel negativefeedback regulator of PASMC proliferation through inhibition of the signal transducer and activator of transcription 3/Pim-1/nuclear factor of activated T cells axis. Modulation of Nur77 activity may potentially represent a novel therapeutic strategy for the treatment of PAH.Keywords: orphan nuclear receptor Nur77; pulmonary artery hypertension; smooth muscle cells; proliferation; signal transducer and activator of transcription 3 Clinical RelevanceUsing in vitro and in vivo models of pulmonary arterial hypertension (PAH), we demonstrated that the orphan nuclear receptor, Nur77, is substantially increased in proliferative pulmonary artery smooth muscle cells (PASMCs) and the lungs of rats with experimental PAH. Overexpression of Nur77 markedly inhibited 5-hydroxytryptamine-induced PASMC proliferation, phosphorylation of signal transducer and activator of transcription 3, and expression of Pim-1, nuclear factor of activated T cells c2, and survivin. These results implicate critical roles of Nur77 in suppressing PASMC proliferation and the development of experimental PAH.

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