Expression of platelet-derived growth factor B-chain in neointimal smooth muscle cells of balloon injured rabbit femoral arteries

Uchida, K.; Sasahara, Masakiyo; Morigami, Naoki; Hazama, Fumitada; Kinoshita, Masahiko

doi:10.1016/0021-9150(95)05742-0

Cited by 86 publications

(51 citation statements)

References 25 publications

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“…expression, consistent with the pattern of change in expression of these genes in response to vascular injury in vivo (25,42). 2) Expression of PDGF-B chain and PDGF-␤ receptor is upregulated in vascular lesions after balloon injury (32,57) and during atherosclerosis (47,59). Moreover, vascular injury is known to result in increased release of PDGF-BB.…”

Section: Discussionsupporting

confidence: 60%

Platelet-derived growth factor-BB and Ets-1 transcription factor negatively regulate transcription of multiple smooth muscle cell differentiation marker genes

Dandré¹,

Owens²

2004

American Journal of Physiology-Heart and Circulatory Physiology

107

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Dandré, Frédéric, and Gary K. Owens. Platelet-derived growth factor-BB and Ets-1 transcription factor negatively regulate transcription of multiple smooth muscle cell differentiation marker genes. Am J Physiol Heart Circ Physiol 286: H2042-H2051, 2004. First published January 29, 2004 10.1152/ajpheart.00625.2003.-Platelet-derived growth factor (PDGF)-BB, a potent mitogen for mesenchymal cells, also downregulates expression of multiple smooth muscle (SM) cell (SMC)-specific markers. However, there is conflicting evidence whether PDGF-BB represses SMC marker expression at a transcriptional or posttranscriptional level, and little is known regarding the mechanisms responsible for these effects. Results of the present studies provide clear evidence that PDGF-BB treatment strongly repressed SM ␣-actin, SM myosin heavy chain (MHC), and SM22␣ promoters in SMCs. Of major significance for resolving previous controversies in the field, we found PDGF-BB-induced repression of SMC marker gene promoters in subconfluent, but not postconfluent, cultures. Treatment of postconfluent SMCs with a tyrosine phosphatase inhibitor restored PDGF-BB-induced repression, whereas treatment of subconfluent SMCs with a tyrosine kinase blocker abolished PDGF-BB-induced repression, suggesting that a tyrosine phosphorylation event mediates cell density-dependent effects. On the basis of previous observations that Ets-1 transcription factor is upregulated within phenotypically modulated neointimal SMCs, we tested whether Ets-1 would repress SMC marker expression. Consistent with this hypothesis, results of cotransfection experiments indicated that Ets-1 overexpression reduced transcriptional activity of SMC marker promoter constructs in SMCs, whereas it increased activity of SM ␣-actin promoter in endothelial cells. PDGF-BB treatment increased expression of Ets-1 in cultured SMCs, and SM ␣-actin mRNA expression was reduced in multiple independent clones of SMCs stably transfected with an Ets-1-overexpressing construct. Taken together, results of these experiments provide novel insights regarding possible mechanisms whereby PDGF-BB and Ets-1 may contribute to SMC phenotypic switching associated with vascular injury. vascular injury; promoter; cell density; signaling SMOOTH MUSCLE (SM) cells (SMCs) are highly specialized cells expressing a unique repertoire of contractile proteins, ion channels, and signaling molecules necessary for their contractile function (38). The differentiation state of SMCs is controlled by a complex combination of local environmental cues such as cell-cell and cell-matrix interactions, neuronal influences, and hemodynamic and mechanical forces (38), as well as intrinsic factors such as clonal origins (6). In contrast to cardiac and skeletal muscle cells, which are terminally differentiated, SMCs can undergo major changes in phenotype, depending on physiological or pathological conditions. For example, in tissue culture or in vascular neointimal lesions, SMCs display diminished expression of a number of proteins that are c...

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Section: Discussionsupporting

confidence: 60%

Platelet-derived growth factor-BB and Ets-1 transcription factor negatively regulate transcription of multiple smooth muscle cell differentiation marker genes

Dandré¹,

Owens²

2004

American Journal of Physiology-Heart and Circulatory Physiology

107

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“…In atherosclerotic lesions, VSMCs are exposed to mitogenic substances such as PDGF (Cui et al, 1998;Gutstein et al, 1999). Moreover, the association between PDGF and VSMC proliferation has been demonstrated in animal experiments, in which increases and augmentations of PDGF-BB after arterial injury were found to be correlated with neointimal cellular proliferation (Uchida et al, 1996). In the present study, we investigated the inhibitory effect of epothilone B on FBS-and PDGF-BB-induced VSMC proliferation and a possible sig- Fig.…”

Section: Discussionmentioning

confidence: 89%

Epothilone B Inhibits Neointimal Formation after Rat Carotid Injury through the Regulation of Cell Cycle-Related Proteins

Lim

Kim²,

Jin³

et al. 2007

J Pharmacol Exp Ther

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The abnormal proliferation of vascular smooth muscle cells (VSMCs) in arterial walls is an important pathogenetic factor of vascular disorders such as atherosclerosis and restenosis after angioplasty. Epothilone B, a novel potential antitumor compound, has a potent effect on preventing postangioplasty restenosis. Therefore, we established an in vivo rat carotid injury model and examined the potential effects of epothilone B on cardiovascular disease. We found that epothilone B potently prevented neointimal formation and in vivo VSMCs proliferation. In addition, we also showed that epothilone B significantly inhibited 5% fetal bovine serum (FBS)-and 50 ng/ml plateletderived growth factor (PDGF)-BB-induced proliferation and cell cycle progression in rat aortic VSMCs. Furthermore, FBS and PDGF-BB induced the activations of extracellular signal-regulated kinases 1 and 2, Akt, phospholipase C ␥ 1, and PDGFreceptor ␤ chain tyrosine kinase were not changed by epothilone B. However, epothilone B treatment caused a significant decrease in the level of cyclin-dependent protein kinase (CDK) 2, whereas it caused no change in the levels of cyclin E and down-regulated the phosphorylation of retinoblastoma, which plays a critical role in cell cycle regulation. Furthermore, levels of p27, an inhibitor of cyclin E/CDK2 complex, were significantly increased in VSMCs treated with epothilone B, indicating that this might be a major molecular mechanism for the inhibitory effects of epothilone B on the proliferation and cell cycle of VSMCs. These findings suggest that epothilone B can inhibit neointimal formation via the cell cycle arrest by the regulation of the cell cycle-related proteins in VSMCs.Proliferation and migration of vascular smooth muscle cells (VSMCs) play a pivotal role in the development of restenosis and in the progression of atherosclerosis (Ross, 1993). Arterial injury results in the migration of VSMCs into the intimal layer of the arterial wall, where they proliferate and synthesize extracellular matrix components. Many growth factors induce the proliferation of VSMCs in vitro and in vivo. Among them, platelet-derived growth factor (PDGF) and basic fibroblast growth factor are important regulators of VSMC behavior through their well defined actions as potent chemoattractants and strong mitogens. Administration of these growth factors enhances intimal thickening after angioplasty in rat, whereas injection of antibodies or use of antisense technology to block signal transduction by either of these growth factors potently inhibits postinjury intimal hyperplasia in rat and restenosis in pig, suggesting that VSMC growth plays an important role in the pathogenesis of these models.Arterial injury during percutaneous transluminal coronary angioplasty induces multiple signaling pathways that activate VSMC migration and proliferation. Immediately after injury, VSMCs leave their quiescent state and enter the cell

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“…Although all these factors may play a role in driving the early cellular events leading to restenosis, it is generally accepted that PDGF, appears to play an important role in neointimal proliferation and development of restenosis [45]. The association between PDGF and vascular SMC proliferation has been demonstrated in animal experiments in which the increasing levels of PDGF after arterial injury correlated with neointimal cellular proliferation [45]. Besides stimulating cell growth, PDGF also can induce migration in SMCs, as PDGF is the strongest reported chemoattractant for vascular SMCs [46].…”

Section: Discussionmentioning

confidence: 99%

Berberine suppresses MEK/ERK-dependent Egr-1 signaling pathway and inhibits vascular smooth muscle cell regrowth after in vitro mechanical injury

Liang

Ting

Yin

et al. 2006

Biochemical Pharmacology

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Vascular smooth muscle cell (SMC) proliferation plays an important role in the pathogenesis of atherosclerosis and post-angioplasty restenosis. Berberine is a well-known component of the Chinese herb medicine Huanglian (Coptis chinensis), and is capable of inhibiting SMC contraction and proliferation, yet the exact mechanism is unknown. We therefore investigated the effect of berberine on SMC growth after mechanic injury in vitro. DNA synthesis and cell proliferation assay were performed to show that berberine inhibited serum-stimulated rat aortic SMC growth in a concentration-dependent manner. Mechanical injury with sterile pipette tip stimulated the regrowth of SMCs. Treatment with berberine prevented the regrowth and migration of SMCs into the denuded trauma zone. Western blot analysis showed that activation of the MEK1/2 (mitogen-activated protein kinase kinase 1/2), extracellular signal-regulated kinase (ERK), and up-regulation of early growth response gene (Egr-1), c-Fos and Cyclin D1 were observed sequentially after mechanic injury in vitro. Semi-quantitative reverse-transcription PCR assay further confirmed the increase of Egr-1, cFos, platelet-derived growth factor (PDGF) and Cyclin D1 expression in a transcriptional level. However, berberine significantly attenuated MEK/ERK activation and downstream target (Egr-1, cFos, Cyclin D1 and PDGF-A) expression after mechanic injury in vitro. Our study showed that berberine blocked injury-induced SMC regrowth by inactivation of ERK/Egr-1 signaling pathway thereby preventing early signaling induced by injury in vitro. The anti-proliferative properties of berberine may be useful in treating disorders due to inappropriate SMC growth.

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Expression of platelet-derived growth factor B-chain in neointimal smooth muscle cells of balloon injured rabbit femoral arteries

Cited by 86 publications

References 25 publications

Platelet-derived growth factor-BB and Ets-1 transcription factor negatively regulate transcription of multiple smooth muscle cell differentiation marker genes

Platelet-derived growth factor-BB and Ets-1 transcription factor negatively regulate transcription of multiple smooth muscle cell differentiation marker genes

Epothilone B Inhibits Neointimal Formation after Rat Carotid Injury through the Regulation of Cell Cycle-Related Proteins

Berberine suppresses MEK/ERK-dependent Egr-1 signaling pathway and inhibits vascular smooth muscle cell regrowth after in vitro mechanical injury

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