Distinct Regulation of Mitogen-activated Protein Kinases and p27Kip1 in Smooth Muscle Cells from Different Vascular Beds

Castro, Claudia; Dı́ez-Juan, Antonio; Cortés, María José García; Andrés, Vicente

doi:10.1074/jbc.m204716200

Cited by 44 publications

(37 citation statements)

References 53 publications

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“…Indeed, in a previous study, overexpression of p27 kip1 was reported to inhibit VSMC growth (74). Here, we show that whereas all three agonists (PDGF-BB, TNF-␣, and IGF-1) induced phosphorylation and nuclear exclusion in VSMC, only PDGF-BB had a significant inhibitory effect on p27 kip1 .…”

Section: Discussionmentioning

confidence: 42%

Forkhead Transcription Factors Inhibit Vascular Smooth Muscle Cell Proliferation and Neointimal Hyperplasia

Abid

Yano

Guo

et al. 2005

Journal of Biological Chemistry

113

107

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Vascular smooth muscle cell (VSMC) proliferation and migration contribute significantly to atherosclerosis, postangioplasty restenosis, and transplant vasculopathy. Forkhead transcription factors belonging to the FoxO subfamily have been shown to inhibit growth and cell cycle progression in a variety of cell types. We hypothesized that forkhead proteins may play a role in VSMC biology. Under in vitro conditions, platelet-derived growth factor (PDGF)-BB, tumor necrosis factor-␣, and insulin-like growth factor 1 stimulated phosphorylation of FoxO in human coronary artery smooth muscle cells via MEK1/2 and/or phosphatidylinositol 3-kinasedependent signaling pathways. PDGF-BB, tumor necrosis factor-␣, and insulin-like growth factor 1 treatment resulted in the nuclear exclusion of FoxO, whereas PDGF-BB alone down-regulated the FoxO target gene, p27 kip1 , and enhanced cell survival and progression through the cell cycle. These effects were abrogated by overexpression of a constitutively active, phosphorylation-resistant mutant of the FoxO family member, TM-FKHRL1. The anti-proliferative effect of TM-FKHRL1 was partially reversed by small interfering RNA against p27 kip1 . In a rat balloon carotid arterial injury model, adenovirus-mediated gene transfer of FKHRL1 caused an increase in the expression of p27 kip1 in the VSMC and inhibition of neointimal hyperplasia. These data suggest that FoxO activity inhibits VSMC proliferation and activation and that this signaling axis may represent a therapeutic target in vasculopathic disease states.

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Section: Discussionmentioning

confidence: 42%

Forkhead Transcription Factors Inhibit Vascular Smooth Muscle Cell Proliferation and Neointimal Hyperplasia

Abid

Yano

Guo

et al. 2005

Journal of Biological Chemistry

113

107

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“…The protective role of p27 kip1 against neointimal thickening has been also demonstrated in hypercholesterolemic apolipoprotein-deficient mice in which genetic inactivation of one or both p27 kip1 alleles shows progressively accelerated atherosclerosis (56,69,70). 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).…”

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

confidence: 85%

“…Although not tested in this work, the MAPK pathway has been shown to have effect on cellular p27 kip1 levels in VSMC. Pharmacological inhibition of MAPKs increased p27 kip1 expression and attenuated VSMC proliferation and migration (72). MAPK cascade has also shown to be required for p27 kip1 down-regulation and S phase entry in fibroblasts and epithelial cells (80).…”

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

confidence: 99%

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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“…It is possible that p27Kip1 may also be a downstream effector of AGGF1‐ERK signaling. Inhibition of ERK1/2 by specific inhibitors or overexpression of dominant negative ERK inhibits PDGF‐induced downregulation of p27Kip1 61, 62. p27Kip1 is a cyclin‐dependent kinase inhibitor that regulates cell cycle progression and cell proliferation 63.…”

Section: Discussionmentioning

confidence: 99%

Targeting AGGF1 (angiogenic factor with G patch and FHA domains 1) for Blocking Neointimal Formation After Vascular Injury

Yao

et al. 2017

JAHA

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BackgroundDespite recent improvements in angioplasty and placement of drug‐eluting stents in treatment of atherosclerosis, restenosis and in‐stent thrombosis impede treatment efficacy and cause numerous deaths. Research efforts are needed to identify new molecular targets for blocking restenosis. We aim to establish angiogenic factor AGGF1 (angiogenic factor with G patch and FHA domains 1) as a novel target for blocking neointimal formation and restenosis after vascular injury.Methods and Results AGGF1 shows strong expression in carotid arteries; however, its expression is markedly decreased in arteries after vascular injury. AGGF1+/− mice show increased neointimal formation accompanied with increased proliferation of vascular smooth muscle cells (VSMCs) in carotid arteries after vascular injury. Importantly, AGGF1 protein therapy blocks neointimal formation after vascular injury by inhibiting the proliferation and promoting phenotypic switching of VSMCs to the contractile phenotype in mice in vivo. In vitro, AGGF1 significantly inhibits VSMCs proliferation and decreases the cell numbers at the S phase. AGGF1 also blocks platelet‐derived growth factor‐BB–induced proliferation, migration of VSMCs, increases expression of cyclin D, and decreases expression of p21 and p27. AGGF1 inhibits phenotypic switching of VSMCs to the synthetic phenotype by countering the inhibitory effect of platelet‐derived growth factor‐BB on SRF expression and the formation of the myocardin/SRF/CArG‐box complex involved in activation of VSMCs markers. Finally, we show that AGGF1 inhibits platelet‐derived growth factor‐BB–induced phosphorylation of MEK1/2, ERK1/2, and Elk phosphorylation involved in the phenotypic switching of VSMCs, and that overexpression of Elk abolishes the effect of AGGF1.Conclusions AGGF1 protein therapy is effective in blocking neointimal formation after vascular injury by regulating a novel AGGF1‐MEK1/2‐ERK1/2‐Elk‐myocardin‐SRF/p27 signaling pathway.

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Distinct Regulation of Mitogen-activated Protein Kinases and p27Kip1 in Smooth Muscle Cells from Different Vascular Beds

Cited by 44 publications

References 53 publications

Forkhead Transcription Factors Inhibit Vascular Smooth Muscle Cell Proliferation and Neointimal Hyperplasia

Forkhead Transcription Factors Inhibit Vascular Smooth Muscle Cell Proliferation and Neointimal Hyperplasia

Regulation of Vascular Smooth Muscle Proliferation by Heparin

Targeting AGGF1 (angiogenic factor with G patch and FHA domains 1) for Blocking Neointimal Formation After Vascular Injury

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