Inhibition of Vascular Smooth Muscle Cell Proliferation by Sodium Salicylate Mediated by Upregulation of p21
            <sup>Waf1</sup>
            and p27
            <sup>Kip1</sup>

Marra, Diego E.; Simoncini, Tommaso; Liao, James K.

doi:10.1161/01.cir.102.17.2124

Cited by 105 publications

(111 citation statements)

References 37 publications

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“…The inhibitory effect of PDGF on p27 expression has been demonstrated previously in rat aortic SMCs (11) as well as human saphenous vein SMCs (12). Similar down-regulation of p27 is also induced by serum but not by angiotensin (12,31).…”

Section: Figsupporting

confidence: 70%

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PDGF-BB Regulates p27 Expression through ERK-dependent RNA Turn-over inVascular Smooth MuscleCells

Sakakibara

Kubota

Worku

et al. 2005

Journal of Biological Chemistry

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Cyclin-dependent kinase inhibitor p27, a critical determinant for cell cycle progression, is an important regulation target of mitogenic signals during arterial injury. In this study, we show in rat aortic smooth muscle cells that PDGF-BB down-regulated p27 protein and mRNA in an ERK-dependent mechanism. Inhibition of ERK, but not other subtypes of the mitogen-activated protein kinase family, prevented the reduction of p27 protein and mRNA. Conversely, direct activation of ERK via adenovirus-mediated expression of a constitutively active form of MEK led to a reduction of p27 protein and mRNA, further supporting the central role of ERK in regulation of p27 expression. Rapamycin, which potently inhibited PDGF-induced activation of p70 S6 kinase as well as proliferation of smooth muscle cells, did not alter the expression of p27. To delineate the molecular mechanism underlying the p27 down-regulation, we examined the effect of PDGF-BB on p27 promoter activity as well as mRNA stability. Stimulation with PDGF-BB significantly shortened the half-life of p27 mRNA without affecting its promoter activity. To further understand the PDGF-stimulated p27 mRNA turnover, we inserted the 5-and/or 3-untranslated regions of p27 cDNA into a non-PDGF-responsive luciferase gene. Only those chimeric genes that contained the 3-untranslated region responded to PDGF-BB with reduced expression. Moreover, inhibition of ERK completely prevented the effect of PDGF on the chimera expression. In summary, our data suggest that p27 is down-regulated by PDGF-BB in vascular smooth muscle cells through an ERK-dependent posttranscriptional mechanism.

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Section: Figsupporting

confidence: 70%

“…Similar down-regulation of p27 is also induced by serum but not by angiotensin (12,31). The inhibitory effect of PDGF and of serum on p27 is consistent with their mitogenic effects in vascular SMC.…”

Section: Figsupporting

confidence: 65%

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PDGF-BB Regulates p27 Expression through ERK-dependent RNA Turn-over inVascular Smooth MuscleCells

Sakakibara

Kubota

Worku

et al. 2005

Journal of Biological Chemistry

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“…p27 kip1 reportedly abrogates the activities of both CDK2 and CDK4 as well as VSMC proliferation in vitro and in vivo after ballooninjury in pig (Tanner et al, 2000). Some drugs that upregulate p27 kip1 expression reportedly exhibit potent anti-proliferative activities on VSMCs (Chen et al, 1997;Marra et al, 2000). Thus, our fi nding that OD78 selectively upregulates p27 kip1 expression is consistent with its greater inhibitory effects on the expression of multiple cell cycle proteins.…”

Section: Figsupporting

confidence: 73%

Anti-Proliferative Activity of OD78 Is Mediated through Cell Cycle Progression by Upregulation p27^kip1in Rat Aortic Vascular Smooth Muscle Cells

Tudev¹,

Lim²,

Park³

et al. 2011

Biomolecules and Therapeutics

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(PDGF)-BB is a potent growth factor produced by platelets, VSMCs, and endothelial cells in the injured vascular wall (Majesky et al., 1990;Miyauchi et al., 1998). PDGF initiates the activation of intracellular signal transduction pathways that contribute to VSMC proliferation, migration, and collagen Atherosclerosis and post-angiography restenosis are associated with intimal thickening and concomitant vascular smooth muscle cell (VSMC) proliferation. Obovatol, a major biphenolic component isolated from the Magnolia obovata leaf, is known to have antiinfl ammatory and anti-tumor activities. The goal of the present study was to enhance the inhibitory effects of obovatol to improve its potential as a preventive or therapeutic agent in atherosclerosis and restenosis. Platelet-derived growth factor (PDGF)-BB-induced proliferation of rat aortic smooth muscle cells (RASMCs) was examined in the presence or absence of a newly synthesized obovatol derivative, OD78. The observed anti-proliferative effect of OD78 was further investigated by cell counting and [ 3 H]-thymidine incorporation assays. Treatment with 1-4 μM OD78 dose-dependently inhibited the proliferation and DNA synthesis of 25 ng/ ml PDGF-BB-stimulated RASMCs. Accordingly, OD78 blocked PDGF-BB-induced progression from the G 0 /G 1 to S phase of the cell cycle in synchronized cells. OD78 decreased the expression levels of CDK4, cyclin E, and cyclin D1 proteins, as well as the phosphorylation of retinoblastoma protein and proliferating cell nuclear antigen; however, it did not change the CDK2 expression level. In addition, OD78 inhibited downregulation of the cyclin-dependent kinase inhibitor (CKI) p27 kip1 . However, OD78 did not affect the CKI p21 cip1 or phosphorylation of early PDGF signaling pathway. These results suggest that OD78 may inhibit PDGF-BBinduced RASMC proliferation by perturbing cell cycle progression, potentially through p27 kip1 pathway activation. Consequently, OD78 may be developed as a potential anti-proliferative agent for the treatment of atherosclerosis and angioplasty restenosis. (Ammon and Wahl, 1991). PDGF-BB propagates mitogenic signals through the autophosphorylation of its respective PDGF beta-receptor (Rβ) on tyrosine residues, thus triggering downstream signal transduction and cell cycle progression (Blenis, 1993;Heldin et al., 1998;Ahn et al., 1999).Cell cycle phases are coordinated by the expression and activation of regulatory proteins, including complexes of cyclins and cyclin-dependent kinases (CDK) (Braun-Dullaeus et al., 1998). The kinase activity of these CDK-cyclin complexes is further negatively regulated by two classes of cyclin-dependent kinase inhibitors (CKIs) (Sherr and Roberts, 1999). INK4 family members (p16 INK4a and p15 INK4b ) inhibit only CDK4 and CDK6 (Ortega et al., 2002), while cip family members (p21 cip1

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“…The migratory response exhibited by VSMC in response to mitogens has been shown to be inhibited by overexpression of p27 kip1 (58,67,71,72). Inhibition of VSMC proliferation by salicylate has also been shown to be mediated by up-regulation of p27 kip1 and p21 (73). Contrary to this finding, neointimal hyperplasia after mechanical damage of the artery wall was comparable in both wild-type and p27 kip1 -null mice (56,74).…”

Section: Fig 5 Heparin Treatment Of Vsmc Increases the Half-life Ofmentioning

confidence: 95%

Regulation of Vascular Smooth Muscle Proliferation by Heparin

Fasciano

Patel

Handy

et al. 2005

Journal of Biological Chemistry

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Uncontrolled proliferation of vascular smooth muscle cells (VSMCs) contribute to intimal hyperplasia during atherosclerosis and restenosis. Heparin is an antiproliferative agent for VSMCs and has been shown to block VSMC proliferation both in tissue culture systems and in animals. Despite the well documented antiproliferative actions of heparin, its cellular targets largely remain unknown. In an effort to characterize the mechanism of the antiproliferative property of heparin, we have analyzed the effect of heparin on cell cycle in VSMC. Our results indicate that the heparin-induced block in G 1 to S phase transition is imposed by p27 kip1 -mediated inhibition of cyclin-dependent kinase 2 activity. Further analysis of p27 kip1 mRNA levels showed that the increase in p27 kip1 protein levels in heparin-treated VSMC occurs at posttranscriptional levels. We present evidence that heparin causes stabilization of p27 kip1 protein during G 1 phase and thereby prevents activation of cyclin-dependent kinase 2.The proliferation of vascular smooth muscle cells (VSMCs) 1 is a key event in the development of atherosclerotic lesions and postangioplasty restenosis (1). In a normal artery, the VSMCs are in a non-proliferative quiescent state and show a well differentiated contractile phenotype. After the vascular injury, there is a loss of differentiated phenotype and a shift to a synthetic phenotype, which is also accompanied by entry into the cell cycle and proliferation (2). Several cytokines, growth factors, vasoregulatory molecules, and extracellular matrix components exert their effects on the proliferation of VSMC. The development of an atherosclerotic lesion can be blocked significantly by effective inhibition of VSMC proliferation (3). Natural glycosaminoglycans such as heparin are also known inhibit VSMC proliferation in vitro in tissue culture (4 -6) and in vivo in animal models (7,8). Despite the well documented antiproliferative effect of heparin on VSMC, the molecular mechanisms responsible for inhibition of cell cycle remain uncharacterized.Cellular proliferation is regulated primarily by regulation of the cell cycle (9), which consists of four distinct sequential phases (G 0 /G 1 , S, G 2 , and M). This tightly regulated temporal order is controlled by the sequential activation of certain serine/threonine protein kinases known as cyclin-dependent kinases (Cdks) that phosphorylate the Rb protein (10). In quiescent cells, Rb exists in its hypophosphorylated state and is thus able to bind and sequester the members of E2F family of transcription factors (11). Phosphorylation of Rb at multiple sites by Cdks causes the release of E2F because hyperphosphorylated Rb cannot bind and sequester E2F factors, thus enabling them to activate transcription of genes whose products are absolutely essential for further cell cycle progression (12). The activity of Cdks is further regulated negatively by a number of Cdk inhibitors, which are grouped into two classes (13) (14), and the members of Cip family (p21 cip1 , p27 kip1 , and ...

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Inhibition of Vascular Smooth Muscle Cell Proliferation by Sodium Salicylate Mediated by Upregulation of p21 ^Waf1 and p27 ^Kip1

Cited by 105 publications

References 37 publications

PDGF-BB Regulates p27 Expression through ERK-dependent RNA Turn-over inVascular Smooth MuscleCells

PDGF-BB Regulates p27 Expression through ERK-dependent RNA Turn-over inVascular Smooth MuscleCells

Anti-Proliferative Activity of OD78 Is Mediated through Cell Cycle Progression by Upregulation p27^kip1in Rat Aortic Vascular Smooth Muscle Cells

Regulation of Vascular Smooth Muscle Proliferation by Heparin

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Inhibition of Vascular Smooth Muscle Cell Proliferation by Sodium Salicylate Mediated by Upregulation of p21 Waf1 and p27 Kip1

Cited by 105 publications

References 37 publications

PDGF-BB Regulates p27 Expression through ERK-dependent RNA Turn-over inVascular Smooth MuscleCells

PDGF-BB Regulates p27 Expression through ERK-dependent RNA Turn-over inVascular Smooth MuscleCells

Anti-Proliferative Activity of OD78 Is Mediated through Cell Cycle Progression by Upregulation p27kip1in Rat Aortic Vascular Smooth Muscle Cells

Regulation of Vascular Smooth Muscle Proliferation by Heparin

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Inhibition of Vascular Smooth Muscle Cell Proliferation by Sodium Salicylate Mediated by Upregulation of p21 ^Waf1 and p27 ^Kip1

Anti-Proliferative Activity of OD78 Is Mediated through Cell Cycle Progression by Upregulation p27^kip1in Rat Aortic Vascular Smooth Muscle Cells