An Essential Role for gp130 in Neointima Formation Following Arterial Injury

Wang, Dong; Liu, Zhimin; Li, Quanyi; Karpurapu, Manjula; Kundumani‐Sridharan, Venkatesh; H, Cao; Dronadula, Nagadhara; Rizvi, Farhan; Bajpai, Arun K.; Zhang, Chunxiang; Müller‐Newen, Gerhard; Harris, Kevin W.; Rao, Gadiparthi N.

doi:10.1161/01.res.0000261350.61711.9e

Cited by 50 publications

(48 citation statements)

References 43 publications

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“…44,45 In addition, we recently reported that cyclin D1 mediates SMC migration induced by interleukin-6 and balloon injury. 46 These findings suggest that cyclin D1, in addition to its role in cell-cycle regulation, is involved in the modulation of cell motility. Although cyclin D1 seems to be one of the molecules required for cell-cycle progression, and possibly cell migration, other molecules whose actions are required for cell proliferation and migration may also be targets of STAT-5B in VSMCs.…”

Section: Figurementioning

confidence: 95%

Suppression of Activation of Signal Transducer and Activator of Transcription-5B Signaling in the Vessel Wall Reduces Balloon Injury-Induced Neointima Formation

Kundumani‐Sridharan

Wang

Karpurapu

et al. 2007

The American Journal of Pathology

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Previously, we have demonstrated that STAT-5B plays a role in thrombin-induced vascular smooth muscle cell (VSMC) growth and motility. To learn more about the role of STAT-5B in vessel wall remodeling, we examined its involvement in platelet-derived growth factor-BB (PDGF-BB)-stimulated VSMC growth and motility and balloon injury-induced neointima formation. PDGF-BB activated STAT-5B as measured by its tyrosine phosphorylation, DNA binding, and reporter gene activity. PDGF-BB induced cyclin D1 expression, CDK4 activity, and Rb protein phosphorylation, leading to VSMC growth and motility, and these responses were suppressed by the blockade of STAT-5B. Increased cyclin D1 levels, CDK4 activity, and Rb protein phosphorylation were observed in 1-week balloon-injured arteries compared with uninjured arteries, and these responses were also suppressed by adenovirus-mediated expression of dnSTAT-5B. In addition, adenovirus-mediated expression of dnSTAT-5B attenuated balloon injury-induced smooth muscle cell migration from media to intima and their proliferation in intima, resulting in reduced neointima formation. These observations indicate that STAT-5B plays an important role in PDGF-BB-induced VSMC growth and motility in vitro and balloon injury-induced neointima formation in vivo. (Am J

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Section: Figurementioning

confidence: 95%

Suppression of Activation of Signal Transducer and Activator of Transcription-5B Signaling in the Vessel Wall Reduces Balloon Injury-Induced Neointima Formation

Kundumani‐Sridharan

Wang

Karpurapu

et al. 2007

The American Journal of Pathology

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“…BI was performed essentially as described previously (28). Briefly, rats weighing 250 -300 g were anesthetized by injecting (intraperitoneally) ketamine (60 mg/kg) and xylazine (5 mg/kg).…”

Section: Transient Transfections and Luciferasementioning

confidence: 99%

“…Delivery of Adenoviruses into Injured Arteries-After balloon injury, solutions of 100 l of Ad-GFP (10 10 plaque-forming units/ml), Ad-VIVIT (10 10 plaque-forming units/ml), or Adcyclin D1 (10 10 plaque-forming units/ml) were infused into the ligated segment of the common carotid artery for 30 min as described previously (28).…”

Section: Transient Transfections and Luciferasementioning

confidence: 99%

Cyclin D1 Is a Bona Fide Target Gene of NFATc1 and Is Sufficient in the Mediation of Injury-induced Vascular Wall Remodeling

Karpurapu

Wang

Quyền

et al. 2010

Journal of Biological Chemistry

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Platelet-derived growth factor BB induced cyclin D1 expression in a time-and nuclear factor of activated T cells (NFAT)-dependent manner in human aortic smooth muscle cells (HASMCs), and blockade of NFATs prevented HASMC DNA synthesis and their cell cycle progression from G 1 to S phase. Selective inhibition of NFATc1 by its small interfering RNA also blocked HASMC proliferation and migration. Characterization of the cyclin D1 promoter revealed the presence of several NFAT binding sites, and the site at nucleotide ؊1333 was found to be sufficient in mediating platelet-derived growth factor BBinduced cyclin D1 promoter-luciferase reporter gene activity. In addition to its role in cell cycle progression, cyclin D1 mediated HASMC migration in an NFATc1-dependent manner. Balloon injury-induced cyclin D1-CDK4 activity requires NFAT activation, and adenovirus-mediated transduction of cyclin D1 was found to be sufficient to overcome the blockade effect of NFATs by VIVIT on balloon injury-induced vascular wall remodeling events, including smooth muscle cell migration from the medial to luminal region, their proliferation in the intimal region, and neointima formation. Together, these results provide more mechanistic evidence for the role of NFATs, particularly NFATc1, in the regulation of HASMC proliferation and migration as well as vascular wall remodeling. NFATc1 could be a potential therapeutic target against the renarrowing of artery after angioplasty.

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“…Cultures were maintained at 37 °C in a humidified 95% air and 5% CO 2 atmosphere. The experiments were performed by using subcultured vascular smooth muscle cells between 5 and 9 passages by following a previously published paper [23]. The rationale for using subcultured smooth muscle cells isolated from rat aorta is based on the evidence that there are extensive phenotypic similarities among subcultured aortic smooth muscle cells and the cells in neointima.…”

Section: Cell Culturementioning

confidence: 99%

“…Inhibition of excessive IL-6 signaling by blocking the gp130/JAK/STAT pathway has become a promising intervention to reduce inflammation. A recent study reported that vascular injury increased STAT 3 phosphorylation and that blockade of gp130/STAT 3 signaling decreased balloon injury-induced STAT 3 phosphorylation, reduced smooth muscle cell migration from media to intima, and attenuated neointima formation [23], suggesting that IL-6 plays a pivotal role in vascular injury-induced neointima formation by activating gp130/STAT 3 pathway. PTP1B is a non-receptor protein tyrosine phosphatase that serves as a negative regulator in several signal transduction pathways.…”

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confidence: 99%

A Central Role of PTP1B in Hyperinsulinemia-Enhanced IL-6 Signaling in Dedifferentiated Vascular Smooth Muscle Cells

Chang¹

2011

J Diabet Metabol

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Hyperinsulinemia, a major feature of type 2 diabetes and the metabolic syndrome, is believed to be highly associated with the occurrence of atherosclerosis and vascular restenosis [1][2][3]. In humans with insulin resistance, the frequency of restenosis after coronary angioplasty is significantly higher than those with normal insulinemia [4]. Animals with hyperinsulinemia show increased neointima formation caused by vascular injury via potentiating smooth muscle cell migration and proliferation [5][6][7]. The application of insulin sensitizers, such as synthetic thiazolidinediones (STD), significantly reduces carotid artery intima/ media thickness in patients with type 2 diabetes [8][9][10] and in animals with induced carotid injury [11][12][13][14]. However, the underlying mechanisms are not well understood. Recurrent stenosis after angioplasty is the result of increased smooth muscle cell proliferation in the media layer and migration to the intima in the wall of the vasculature. It is well established that vascular inflammation in response to angioplasty-induced injury is the initiator of increased neointima formation. Several experimental and clinical observations indicate that up regulation of pro-inflammatory cytokines in activated SMCs contributes to angioplasty-induced restenosis through promoting vascular smooth muscle cell migration and proliferation, a manifestation of an inflammatory wound healing process occurring in injured vessels [15][16][17]. Of the many cytokines involved in injury-induced inflammation, IL-6 is the major pro-inflammatory cytokine that contributes to vascular injuryinduced neointima thickening [18]. IL-6 is expressed and synthesized by a variety of cell types implicated in intimal hyperplasia. These include endothelial cells, macrophages, and smooth muscle cells. IL-6 induces a motogenic effect on vascular smooth muscle cells [19,20]. A significant correlation between the changes of IL-6 concentrations in the coronary circulation after PTCA and the degree of restenosis has been observed [21]. Monitoring variations in IL-6 has been proposed as an inflammatory marker to detect the early stage of cardiovascular diseases in order to develop a beneficial strategy to prevent the progression of the diseases. It was also reported that IL-6 induced the expression of acute phase proteins and several other cytokines and growth factors [22], suggesting that IL-6 may serve as a major initiator to trigger inflammation cascade responses that later lead to restenosis. One of the signal transduction pathways that mediates IL-6-mediated cellular responses is gp130/JAK/ STAT cascade [19]. The formation of IL-6 and the IL-6 receptor complex promotes the recruitment of gp130, followed by activation of Janus kinase (JAK). Activation of JAKs leads to tyrosine phosphorylation of gp130 and recruitment of STAT 3 . STAT 3 in turn becomes phosphorylated and dimerized, and translocate into the nucleus, where it binds to the target genes and regulates gene transcription and protein expression [19], leading t...

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An Essential Role for gp130 in Neointima Formation Following Arterial Injury

Cited by 50 publications

References 43 publications

Suppression of Activation of Signal Transducer and Activator of Transcription-5B Signaling in the Vessel Wall Reduces Balloon Injury-Induced Neointima Formation

Suppression of Activation of Signal Transducer and Activator of Transcription-5B Signaling in the Vessel Wall Reduces Balloon Injury-Induced Neointima Formation

Cyclin D1 Is a Bona Fide Target Gene of NFATc1 and Is Sufficient in the Mediation of Injury-induced Vascular Wall Remodeling

A Central Role of PTP1B in Hyperinsulinemia-Enhanced IL-6 Signaling in Dedifferentiated Vascular Smooth Muscle Cells

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