Inhibition of cell cycle progression and migration of vascular smooth muscle cells by prostaglandin D2 synthase: resistance in diabetic Goto-Kakizaki rats

2004 ◽  
Vol 287 (5) ◽  
pp. C1273-C1281 ◽  
Author(s):  
Louis Ragolia ◽  
Thomas Palaia ◽  
Tara B. Koutrouby ◽  
John K. Maesaka
Keyword(s):  
Cell Cycle ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Cell Cycle Progression ◽  
Fold Increase ◽  
Wild Type ◽  
Cycle Progression ◽  
And Migration ◽  
Type 2 Diabetic

The regulation of vascular smooth muscle cell (VSMC) proliferation, migration, and apoptosis plays a clear role in the atherosclerotic process. Recently, we reported on the inhibition of the exaggerated growth phenotype of VSMCs isolated from hypertensive rats by lipocalin-type prostaglandin D2 synthase (L-PGDS). In the present study, we report the differential effects of L-PGDS on VSMC cell cycle progression, migration, and apoptosis in wild-type VSMCs vs. those from a type 2 diabetic model. In wild-type VSMCs, exogenously added L-PGDS delayed serum-induced cell cycle progression from the G1 to S phase, as determined by gene array analysis and the decreased protein expressions of cyclin-dependent kinase-2, p21Cip1, and cyclin D1. Cyclin D3 protein expression was unaffected by L-PGDS, although its gene expression was stimulated by L-PGDS in wild-type cells. In addition, platelet-derived growth factor-induced VSMC migration was inhibited by L-PGDS in wild-type cells. Type 2 diabetic VSMCs, however, were resistant to the L-PGDS effects on cell cycle progression and migration. L-PGDS did suppress the hyperproliferation of diabetic cells, albeit through a different mechanism, presumably involving the 2.5-fold increase in apoptosis and the concomitant 10-fold increase of L-PGDS uptake we observed in these cells. We propose that in wild-type VSMCs, L-PGDS retards cell cycle progression and migration, precluding hyperplasia of the tunica media, and that diabetic cells appear resistant to the inhibitory effects of L-PGDS, which consequently may help explain the increased atherosclerosis observed in diabetes.

scholarly journals Blocking circ_UBR4 suppressed proliferation, migration, and cell cycle progression of human vascular smooth muscle cells in atherosclerosis

2021 ◽  
Vol 16 (1) ◽  
pp. 419-430
Author(s):  
Ying Zhang ◽  
Cheng Zhang ◽  
Zongwei Chen ◽  
Meilan Wang
Keyword(s):  
Cell Cycle ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Cell Cycle Progression ◽  
Muscle Cells ◽  
Matrix Metalloproteinase 2 ◽  
Cycle Progression ◽  
And Migration

Abstract The circ_UBR4 (hsa_circ_0010283) is a novel abnormally overexpressed circRNA in oxidized low-density lipoprotein (ox-LDL)-induced model of atherosclerosis (AS) in human vascular smooth muscle cells (VSMCs). However, its role in the dysfunction of VSMCs remains to be further investigated. Here, we attempted to explore its role in ox-LDL-induced excessive proliferation and migration in VSMCs by regulating Rho/Rho-associated coiled-coil containing kinase 1 (ROCK1), a therapeutic target of AS. Expression of circ_UBR4 and ROCK1 was upregulated, whereas miR-107 was downregulated in human AS serum and ox-LDL-induced VSMCs. Depletion of circ_UBR4 arrested cell cycle, suppressed cell viability, colony-forming ability, and migration ability, and depressed expression of proliferating cell nuclear antigen and matrix metalloproteinase 2 in VSMCs in spite of the opposite effects of ox-LDL. Notably, ROCK1 upregulation mediated by plasmid transfection or miR-107 deletion could counteract the suppressive role of circ_UBR4 knockdown in ox-LDL-induced VSMCs proliferation, migration, and cell cycle progression. In mechanism, miR-107 was identified as a target of circ_UBR4 to mediate the regulatory effect of circ_UBR4 on ROCK1. circ_UBR4 might be a contributor in human AS partially by regulating VSMCs’ cell proliferation, migration, and cell cycle progression via circ_UBR4/miR-107/ROCK1 pathway.

scholarly journals A Dominant-Negative PPARγMutant Promotes Cell Cycle Progression and Cell Growth in Vascular Smooth Muscle Cells

PPAR Research ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-10 ◽  
Author(s):  
Joey Z. Liu ◽  
Christopher J. Lyon ◽  
Willa A. Hsueh ◽  
Ronald E. Law
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Cell Cycle Progression ◽  
Muscle Cells ◽  
Dominant Negative ◽  
Wild Type ◽  
Cycle Progression ◽  
Positive Regulators

PPARγligands have been shown to have antiproliferative effects on many cell types. We herein report that a synthetic dominant-negative (DN) PPARγmutant functions like a growth factor to promote cell cycle progression and cell proliferation in human coronary artery smooth muscle cells (CASMCs). In quiescent CASMCs, adenovirus-expressed DN-PPARγpromoted G1→S cell cycle progression, enhanced BrdU incorporation, and increased cell proliferation. DN-PPARγexpression also markedly enhanced positive regulators of the cell cycle, increasing Rb and CDC2 phosphorylation and the expression of cyclin A, B1, D1, and MCM7. Conversely, overexpression of wild-type (WT) or constitutively-active (CA) PPARγinhibited cell cycle progression and the activity and expression of positive regulators of the cell cycle. DN-PPARγexpression, however, did not up-regulate positive cell cycle regulators in PPARγ-deficient cells, strongly suggesting that DN-PPARγeffects on cell cycle result from blocking the function of endogenous wild-type PPARγ. DN-PPARγexpression enhanced phosphorylation of ERK MAPKs. Furthermore, the ERK specific-inhibitor PD98059 blocked DN-PPARγ-induced phosphorylation of Rb and expression of cyclin A and MCM7. Our data thus suggest that DN-PPARγpromotes cell cycle progression and cell growth in CASMCs by modulating fundamental cell cycle regulatory proteins and MAPK mitogenic signaling pathways in vascular smooth muscle cells (VSMCs).

Abstract 1701: Deletion of β PDGF Receptor Dependent PI-3 Kinase and PLCγ Signaling Attenuates Vascular Smooth Muscle Cell Proliferation and Inhibits Neointima Formation in Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Evren Caglayan ◽  
Marius Vantler ◽  
Olli Leppanen ◽  
Lenard Mustafov ◽  
Felix Gerhardt ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Balloon Angioplasty ◽  
Cell Cycle Progression ◽  
Signaling Molecules ◽  
Brdu Incorporation ◽  
Neointima Formation ◽  
Cycle Progression ◽  
Vsmc Proliferation

Platelet-derived growth factor β-receptor (βPDGFR)-mediated proliferation of vascular smooth muscle cells (VSMC) plays a pivotal role in the development of restenosis. The βPDGFR binds and activates cytoplasmic signaling molecules such as Src, PI 3-kinase (PI3K), RasGAP, SHP-2 and phospholipase C-gamma (PLCγ). However, the βPDGFR-induced signaling pathways leading to cell cycle progression are largely unknown. In order to characterize the signaling molecules, which are important for βPDGFR-induced VSMC proliferation, we generated several stable VSMC lines with mutated βPDGFRs which were unable to bind/activate each individual signaling molecule. BrdU incorporation assays revealed PI3K and PLCγ as the main mediators of βPDGFR-mediated VSMC proliferation. Deletion of the binding sites for PI3K or PLCγ diminished DNA-synthesis about 47 ± 6% and 54 ± 5%, respectively, whereas the deletion of Src, RasGAP, or SHP-2 binding to the βPDGFR had no influence on the mitogenic response. Mutant cell lines which were only able to bind/activate PI3K or PLCγ induced 43 ± 4% and 52 ± 5% of the WT response, respectively. We further investigated the influence of PI3K and PLCγ on the distinct expression of the key players of cell cycle progression. Western blot analysis revealed that βPDGFR-activated PI3K mainly mediated the up-regulation of cyclin D1, whereas activation of PLCγ mediated the down-regulation of the cyclin-dependent kinase-inhibitor p27 kip1 . Consistently, βPDGFR-dependent phosphorylation of the retinoblastoma protein which is important for the G1/S transition was attenuated when either the binding of PI3K or PLCγ to the βPDGFR was abolished. Moreover, we confirmed our in vitro results in an in vivo model of balloon-induced carotid artery neointima formation. Mice lacking binding of PI3K and PLCγ to the βPDGFR (F3 mice) developed ~50% less neointima formation after balloon angioplasty compared to control WT mice after 3 weeks (p < 0.05). These results indicate that the mitogenic signal of the β PDGFR is mediated by PI3K and PLCγ affecting distinct targets of cell cycle progression. Targeting specific downstream molecules of the βPDGFR in VSMCs might provide a novel approach to reduce neointima formation in patients undergoing balloon angioplasty.

Inhibition of vascular smooth muscle cell proliferation by chronic hemin treatment

2008 ◽  
Vol 295 (3) ◽  
pp. H999-H1007 ◽  
Author(s):  
Tuanjie Chang ◽  
Lingyun Wu ◽  
Rui Wang
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Cell Cycle Progression ◽  
Control Level ◽  
Inhibitory Effect ◽  
Cycle Progression ◽  
Vsmc Proliferation ◽  
Long Term Treatment

Hemin, an oxidized form of heme, is an essential regulator of gene expression and cell cycle progression. Our laboratory previously reported ( 34 ) that chronic hemin treatment of spontaneously hypertensive rats reversed the eutrophic inward remodeling of small peripheral arteries. Whether long-term treatment of cultured vascular smooth muscle cells (VSMCs) with hemin alters the proliferation status of these cells has been unknown. In the present study, hemin treatment at 5 μM for 4, 7, 14, and 21 days significantly inhibited the proliferation of cultured rat aortic VSMCs (A-10 cells) by arresting cells at G0/G1 phases so as to decelerate cell cycle progression. Heme oxygenase (HO) activity and inducible HO-1 protein expression were significantly increased by hemin treatment. HO inhibitor tin protoporphyrin IX (SnPP) abolished the effects of hemin on cell proliferation and HO activity. Interestingly, hemin-induced HO-1 expression was further increased in the presence of SnPP. Hemin treatment had no significant effect on the expression of constitutive HO-2. Expression of p21 protein and the level of reactive oxygen species (ROS) were decreased by hemin treatment, which was reversed by application of SnPP. After removal of hemin from culture medium, inhibited cell proliferation and increased HO-1 expression in VSMCs were returned to control level within 1 wk. Transfection with HO-1 small interfering RNA significantly knocked down HO-1 expression and decreased HO activity, but had no effect on HO-2 expression, in cells treated with or without hemin for 7 days. The inhibitory effect of hemin on cell proliferation was abolished in HO-1 silenced cells. It is concluded that induction of HO-1 and, consequently, increased HO activity are responsible for the chronic inhibitory effect of hemin on VSMC proliferation. Changes in the levels of p21 and ROS might also participate in the cellular effects of hemin.

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