scholarly journals An essential role of p27 downregulation in fenvalerate-induced cell growth in human uterine leiomyoma and smooth muscle cells

2012 ◽  
Vol 303 (8) ◽  
pp. E1025-E1035 ◽  
Author(s):  
Xiaohua Gao ◽  
Linda Yu ◽  
Lysandra Castro ◽  
Charles J. Tucker ◽  
Alicia B. Moore ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Uterine Leiomyoma ◽  
Muscle Cells ◽  
S Phase ◽  
Total Cell ◽  
Brdu Incorporation ◽  
Mrna Levels ◽  
Cell Numbers

Previously, we reported that fenvalerate (Fen) promotes proliferation of human uterine leiomyoma (UtLM) cells by enhancing progression of cells from G0-G1to S phase through molecular mechanisms independent of estrogen receptor-α and -β. The cyclin-dependent kinase (CDK) inhibitor p27, which blocks G1to S phase transitions and is an important regulator of CDK2, is often decreased in hormonally regulated diseases, including uterine leiomyomas. Therefore, we were interested in whether Fen could regulate the expression of p27 and whether p27 might play a role in Fen-induced cell proliferation. Expression of p27 in Fen-treated UtLM and uterine smooth muscle cells (UtSMCs) was examined. We found that p27 mRNA was significantly downregulated and that protein levels were decreased in both cell types treated with 10 μM Fen for 24 h compared with respective controls. Overexpression of p27 in UtLM cells and UtSMCs using an adenovirus doxycycline (Dox)-regulated Tet-off system abrogated the proliferative effects of Fen, as evidenced by decreased total cell numbers and BrdU incorporation. Fen treatment increased CDK2 mRNA expression levels; however, overexpression of p27 also abolished this effect. In contrast, Dox treatment dramatically restored the above muted responses. Finally, we utilized siRNA to knock down p27 expression. After transfection, mRNA levels of p27 were downregulated in UtLM cells and UtSMCs and total cell numbers and BrdU incorporation increased significantly compared with nontransfected cells. Fen treatment in the presence of p27 silencing enhanced the increased cell counts and BrdU labeling in UtLM cells and UtSMCs. Taken together, these results indicate that p27 downregulation is critical for Fen-induced cell proliferation.

scholarly journals EDNRA variants associate with smooth muscle mRNA levels, cell proliferation rates, and cystic fibrosis pulmonary disease severity

2010 ◽  
Vol 41 (1) ◽  
pp. 71-77 ◽  
Author(s):  
Rebecca Darrah ◽  
Edward McKone ◽  
Clare O'Connor ◽  
Christine Rodgers ◽  
Alan Genatossio ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Cell Proliferation ◽  
Smooth Muscle ◽  
Pulmonary Function ◽  
Smooth Muscle Cells ◽  
Pulmonary Disease ◽  
Muscle Cells ◽  
Airway Smooth Muscle Cells ◽  
Mrna Levels ◽  
Protective Allele

Airway inflammation and pulmonary disease are heterogeneous phenotypes in cystic fibrosis (CF) patients, even among patients with the same cystic fibrosis transmembrane conductance regulator (CFTR) genotype. Endothelin, a proinflammatory peptide and smooth muscle agonist, is increased in CF airways, potentially contributing to the pulmonary phenotype. Four cohorts of CF patients were screened for variants in endothelin pathway genes to determine whether any of these variants associated with pulmonary function. An initial cohort of 808 CF patients homozygous for the common CF mutation, ΔF508, showed significant association for polymorphisms in the endothelin receptor A gene, EDNRA ( P = 0.04), but not in the related endothelin genes ( EDN1, EDN2, EDN3, or EDNRB) or NOS1, NOS2A, or NOS3. Variants within EDNRA were examined in three additional cohorts of CF patients, 238 patients from Seattle, WA, 303 from Ireland and the U.K., and 228 from Cleveland, OH, for a total of 1,577 CF patients. The three additional groups each demonstrated a significant association between EDNRA 3′-untranslated region (UTR) variant rs5335 and pulmonary function ( P = 0.002). At the molecular level, single nucleotide primer extension assays suggest that the effect of the variants is quantitative. EDNRA mRNA levels from cultured primary tracheal smooth muscle cells are greater for the allele that appears to be deleterious to lung function than for the protective allele, suggesting a mechanism by which increased receptor function is harmful to the CF airway. Finally, cell proliferation studies using human airway smooth muscle cells demonstrated that cells homozygous for the deleterious allele proliferate at a faster rate than those homozygous for the protective allele.

scholarly journals Extracellular Matrix Collagen Alters Cell Proliferation and Cell Cycle Progression of Human Uterine Leiomyoma Smooth Muscle Cells

PLoS ONE ◽  
2013 ◽  
Vol 8 (9) ◽  
pp. e75844 ◽  
Author(s):  
Faezeh Koohestani ◽  
Andrea G. Braundmeier ◽  
Arash Mahdian ◽  
Jane Seo ◽  
JiaJia Bi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Extracellular Matrix ◽  
Cell Proliferation ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Uterine Leiomyoma ◽  
Cell Cycle Progression ◽  
Muscle Cells ◽  
Cycle Progression

Involvement of Cyclooxygenase- and Lipoxygenase-Mediated Conversion of Arachidonic Acid in Controlling Human Vascular Smooth Muscle Cell Proliferation

1990 ◽  
Vol 63 (02) ◽  
pp. 291-297 ◽  
Author(s):  
Herm-Jan M Brinkman ◽  
Marijke F van Buul-Worteiboer ◽  
Jan A van Mourik
Keyword(s):  
Cell Proliferation ◽  
Arachidonic Acid ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Muscle Cells ◽  
Smooth Muscle Cell Proliferation

SummaryWe observed that the growth of human umbilical arterysmooth muscle cells was inhibited by the phospholipase A2 inhibitors p-bromophenacylbromide and mepacrine. Thesefindings suggest that fatty acid metabolism might be integrated in the control mechanism of vascular smooth muscle cell proliferation. To identify eicosanoids possibly involved in this process, we studied both the metabolism of arachidonic acid of these cells in more detail and the effect of certain arachidonic acid metabolites on smooth muscle cells growth. We found no evidence for the conversion of arachidonic acid via the lipoxygenase pathway. In contrast, arachidonic acid was rapidly converted via the cyclooxy-genase pathway. The following metabolites were identified: prostaglandin E2 (PGE2), 6-keto-prostaglandin F1α (6-k-PGF1α), prostaglandin F2α (PGF2α), 12-hydroxyheptadecatrienoic acid (12-HHT) and 11-hydroxyeicosatetetraenoic acid (11-HETE). PGE2 was the major metabolite detected. Arachidonic acid metabolites were only found in the culture medium, not in the cell. After synthesis, 11-HETE was cleared from the culture medium. We have previously reported that PGE2 inhibits the serum-induced [3H]-thymidine incorporation of growth-arrested human umbilical artery smooth muscle cells. Here we show that also 11-HETEexerts this inhibitory property. Thus, our data suggeststhat human umbilical artery smooth muscle cells convert arachidonic acid only via the cyclooxygenase pathway. Certain metabolites produced by this pathway, including PGE2 and 11-HETE, may inhibit vascular smooth muscle cell proliferation.

Ethylisopropylamiloride-sensitive pH control mechanisms modulate vascular smooth muscle cell growth

1991 ◽  
Vol 260 (3) ◽  
pp. C581-C588 ◽  
Author(s):  
A. Bobik ◽  
A. Grooms ◽  
P. J. Little ◽  
E. J. Cragoe ◽  
S. Grinpukel
Keyword(s):  
Cell Cycle ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Mitotic Cell ◽  
Ph Control ◽  
S Phase ◽  
Control Mechanisms ◽  
Aortic Smooth Muscle ◽  
Exchange Activity

The reported effects of alterations in Na-H exchange activity on mitogenesis are variable and appear dependent on the cell type examined. We examined the effects of reductions in ethylisopropylamiloride (EIPA)-sensitive pH-regulating mechanisms including Na-H exchange and alterations in intracellular pH (pHi) on the growth characteristics of rat aortic smooth muscle cells (RASM) cultured in serum-containing bicarbonate-buffered medium. Exposure of RASM replicating in bicarbonate-containing medium to the Na-H exchange inhibitors EIPA, dimethylamiloride (DMA), or amiloride (A) attenuated their replication rate. The order of potency of the inhibitors (EIPA greater than DMA much greater than A) was similar to their documented effects on Na-H exchange activity and to their order of potency for inhibiting recovery from CO2-induced acidosis in these cells. Reductions in pHi induced by lowering extracellular pH also attenuated the incorporation of [3H]-thymidine into DNA, while increases in pHi were associated with an acceleration in the rate of incorporation of [3H]thymidine into DNA. The effects of the Na-H exchange inhibitors on RASM replication were due to a reduction in the ability of the smooth muscle cells to enter the S phase of the mitotic cell cycle. This appeared predominantly the consequence of effects late within the G1 phase of the cell cycle. Concentrations of EIPA that markedly reduced the ability of RASM to enter S phase and to replicate also attenuated the increase in protein synthesis occurring 6-8 h after exposure to serum.(ABSTRACT TRUNCATED AT 250 WORDS)

IL-4 and IL-13 upregulate arginase I expression by cAMP and JAK/STAT6 pathways in vascular smooth muscle cells

2000 ◽  
Vol 279 (1) ◽  
pp. C248-C256 ◽  
Author(s):  
Liu Hua Wei ◽  
Aaron T. Jacobs ◽  
Sidney M. Morris ◽  
Louis J. Ignarro
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Growth ◽  
Muscle Cells ◽  
Protein Levels ◽  
Ifn Γ ◽  
Arginase Ii ◽  
Arginase I

The objectives of this study were to determine whether rat aortic smooth muscle cells (RASMC) express arginase and to elucidate the possible mechanisms involved in the regulation of arginase expression. The results show that RASMC contain basal arginase I (AI) activity, which is significantly enhanced by stimulating the cells with either interleukin (IL)-4 or IL-13, but arginase II (AII) expression was not detected under any condition studied here. We further investigated the signal transduction pathways responsible for AI induction. AI mRNA and protein levels were enhanced by addition of forskolin (1 μM) and inhibited by H-89 (30 μM), suggesting positive regulation of AI by a protein kinase A pathway. Genistein (10 μg/ml) and sodium orthovanadate (Na3VO4; 10 μM) were used to investigate the role of tyrosine phosphorylation in the control of AI expression. Genistein inhibited, whereas Na3VO4enhanced the induction of AI by IL-4 or IL-13. Along with immunoprecipitation and immunoblot analyses, these data implicate the JAK/STAT6 pathway in AI regulation. Dexamethasone (Dex) and interferon (IFN)-γ were investigated for their effects on AI induction. Dex (1 μM) and IFN-γ (100 U/ml) alone had no effect on basal AI expression in RASMC, but both reduced AI induction by IL-4 and IL-13. In combination, Dex and IFN-γ abolished AI induction by IL-4 and IL-13. Finally, both IL-4 and IL-13 significantly increased RASMC DNA synthesis as monitored by [3H]thymidine incorporation, demonstrating that upregulation of AI is correlated with an increase in cell proliferation. Blockade of AI induction by IFN-γ, H-89, or genistein also blocked the increase in cell proliferation. These observations are consistent with the possibility that upregulation of AI might play an important role in the pathophysiology of vascular disorders characterized by excessive smooth muscle growth.

scholarly journals EXPRESS: Ubiquitin‑specific protease 7 mediates platelet derived growth factor-induced pulmonary arterial smooth muscle cells proliferation

2021 ◽  
pp. 204589402110461
Author(s):  
Yanting Zhu ◽  
Qianqian Zhang ◽  
Xin Yan ◽  
Lu Liu ◽  
Cui Zhai ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Growth Factor ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Platelet Derived Growth Factor ◽  
Specific Protease ◽  
Pulmonary Arterial ◽  
Arterial Smooth Muscle Cells ◽  
Pulmonary Arterial Smooth Muscle

Pulmonary arterial hypertension (PAH) is a devastating pulmonary vascular disease, in which the pathogenesis is complicated and unclear. Pulmonary arterial smooth muscle cells (PASMCs) proliferation is a key pathological feature of PAH. It has been shown that ubiquitin-specific protease 7 (USP7) is involved in cancer cell proliferation via deubiquitinating and stabilizing E3 ubiquitin ligase mouse double minute 2 (MDM2). However, the effect of USP7 and MDM2 on platelet derived growth factor (PDGF) -induced PASMCs proliferation is uncertain. This study aims to explore this issue. Our results indicated that PDGF up-regulated USP7 protein expression and stimulated PASMCs proliferation; this was accompanied with the increase of MDM2, forkhead box O4 (FoxO4) reduction and elevation of CyclinD1. While prior transfection of USP7 siRNA blocked PDGF-induced MDM2 up-regulation, FoxO4 down-regulation, increase of CyclinD1 and cell proliferation. Pre-depletion of MDM2 by siRNA transfection reversed PDGF-induced reduction of FoxO4, up-regulation of CyclinD1 and PASMCs proliferation. Furthermore, pre-treatment of cells with proteasome inhibitor MG-132 also abolished PDGF-induced FoxO4 reduction, CyclinD1 elevation and cell proliferation. Our study suggests that USP7 up-regulates MDM2, which facilitates FoxO4 ubiquitinated degradation, and subsequently increases the expression of CyclinD1 to mediate PDGF-induced PASMCs proliferation.

Effects of hypoxia on rat airway smooth muscle cell proliferation

2003 ◽  
Vol 94 (4) ◽  
pp. 1403-1409 ◽  
Author(s):  
A. Cogo ◽  
G. Napolitano ◽  
M. C. Michoud ◽  
D. Ramos Barbon ◽  
M. Ward ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Cell Growth ◽  
Smooth Muscle Cells ◽  
Smooth Muscle Cell ◽  
Airway Smooth Muscle ◽  
Muscle Cell ◽  
Muscle Cells ◽  
Airway Smooth Muscle Cell ◽  
Gf 109203X

Although it is well known that hypoxemia induces pulmonary vasoconstriction and vascular remodeling, due to the proliferation of both vascular smooth muscle cells and fibroblasts, the effects of hypoxemia on airway smooth muscle cells are not well characterized. The present study was designed to assess the in vitro effects of hypoxia (1 or 3% O2) on rat airway smooth muscle cell growth and response to mitogens (PDGF and 5-HT). Cell growth was assessed by cell counting and cell cycle analysis. Compared with normoxia (21% O2), there was a 42.2% increase in the rate of proliferation of cells exposed to 3% O2 (72 h, P = 0.006), as well as an enhanced response to PDGF (13.9% increase; P = 0.023) and to 5-HT (17.2% increase; P = 0.039). Exposure to 1% O2 (72 h) decreased cell proliferation by 21.0% ( P = 0.017) and reduced the increase in cell proliferation induced by PGDF and 5-HT by 16.2 and 15.7%, respectively ( P = 0.019 and P = 0.011). A significant inhibition in hypoxia-induced cell proliferation was observed after the administration of bisindolylmaleimide GF-109203X (a specific PKC inhibitor) or downregulation of PKC with PMA. Pretreatment with GF-109203X decreased proliferation by 21.5% ( P = 0.004) and PMA by 31.5% ( P = 0.005). These results show that hypoxia induces airway smooth muscle cell proliferation, which is at least partially dependent on PKC activation. They suggest that hypoxia could contribute to airway remodeling in patients suffering from chronic, severe respiratory diseases.

scholarly journals Troglitazone and pioglitazone attenuate agonist-dependent Ca2+ mobilization and cell proliferation in vascular smooth muscle cells

1999 ◽  
Vol 128 (3) ◽  
pp. 673-683 ◽  
Author(s):  
Michiko Asano ◽  
Toshiaki Nakajima ◽  
Kuniaki Iwasawa ◽  
Toshihiro Morita ◽  
Fumitaka Nakamura ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells

scholarly journals Relationship between spontaneous Ca2+ oscillations and cell proliferation in cultured longitudinal smooth muscle cells.

1993 ◽  
Vol 61 ◽  
pp. 119
Author(s):  
Megumi Kawanishi ◽  
Hisayuki Ohata ◽  
Kazutaka Momose ◽  
Chikako Uneyama ◽  
Michihito Takahashi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Longitudinal Smooth Muscle
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