The IκB Kinase Inhibitor Nuclear Factor-κB Essential Modulator–Binding Domain Peptide for Inhibition of Injury-Induced Neointimal Formation

Grassia, Gianluca; Maddaluno, Marcella; Musilli, Claudia; Stefano, Daniela De; Carnuccio, Rosa; Lauro, Maria Vittoria Di; Parratt, Christopher A.; Kennedy, Simon; Meglio, Paola Di; Ianaro, Angela; Maffia, Pasquale; Parenti, Astrid; Ialenti, Armando

doi:10.1161/atvbaha.110.215467

Cited by 26 publications

(25 citation statements)

References 35 publications

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“…Activation of NF-κB has been reported to promote vascular smooth muscle cell proliferation and neointima formation19202122. Therefore, prolonged UPR activation under the condition of proliferation of vascular smooth muscle cells would cause vascular inflammation, leading to the development and acceleration of neointima formation.…”

Section: Discussionmentioning

confidence: 99%

Reduction of endoplasmic reticulum stress inhibits neointima formation after vascular injury

Ishimura

Furuhashi

Mita

et al. 2014

Sci Rep

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Endoplasmic reticulum (ER) stress and inappropriate adaptation through the unfolded protein response (UPR) are predominant features of pathological processes. However, little is known about the link between ER stress and endovascular injury. We investigated the involvement of ER stress in neointima hyperplasia after vascular injury. The femoral arteries of 7-8-week-old male mice were subjected to wire-induced vascular injury. After 4 weeks, immunohistological analysis showed that ER stress markers were upregulated in the hyperplastic neointima. Neointima formation was increased by 54.8% in X-box binding protein-1 (XBP1) heterozygous mice, a model of compromised UPR. Knockdown of Xbp1 in human coronary artery smooth muscle cells (CASMC) in vitro promoted cell proliferation and migration. Furthermore, treatment with ER stress reducers, 4-phenylbutyrate (4-PBA) and tauroursodeoxycholic acid (TUDCA), decreased the intima-to-media ratio after wire injury by 50.0% and 72.8%, respectively. Chronic stimulation of CASMC with PDGF-BB activated the UPR, and treatment with 4-PBA and TUDCA significantly suppressed the PDGF-BB-induced ER stress markers in CASMC and the proliferation and migration of CASMC. In conclusion, increased ER stress contributes to neointima formation after vascular injury, while UPR signaling downstream of XBP1 plays a suppressive role. Suppression of ER stress would be a novel strategy against post-angioplasty vascular restenosis.

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Section: Discussionmentioning

confidence: 99%

Reduction of endoplasmic reticulum stress inhibits neointima formation after vascular injury

Ishimura

Furuhashi

Mita

et al. 2014

Sci Rep

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“…[14][15][16] The study showed that at day 28, neointimal lesions in MMP8 knockout mice were significantly smaller than those in MMP8 wild-type mice ( Figure 1A). We also examined cell proliferation in the injured carotid arteries at days 7 and 28, and found that there were significantly fewer proliferating cells in injured carotid arteries in MMP8 knockout mice than in MMP8 wild-type mice at day 7 ( …”

Section: Impact Of Mmp8 On Cell Proliferation and Neointima Formationmentioning

confidence: 95%

Matrix Metalloproteinase-8 Promotes Vascular Smooth Muscle Cell Proliferation and Neointima Formation

Xiao

Zhang

Grassia

et al. 2014

ATVB

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T he pathogenesis of postangioplasty restenosis involves migration and proliferation of vascular smooth muscle cells (VSMCs), which constitute a major component of postangioplasty neointimal lesions.1-4 VSMC migration and proliferation are regulated by growth factors, adhesion molecules, proteases, and intracellular proteins. Among them, the cadherin-β-catenin complex and its cognate intracellular pathway have been increasingly appreciated as important regulators of these processes. 5-8Matrix metalloproteinase-8 (MMP8) was once thought to be produced exclusively by polymorphonuclear leukocytes, but more recent studies have shown that various other cell types including stem/progenitor cells express this protease.9 Compared with some other members of the MMP family, MMP8 has been less investigated for its proteolytic substrates and biological roles. Herman et al 10 were the first to reveal that VSMCs, endothelial cells, and macrophages in atherosclerotic plaques express MMP8. Subsequently other investigators showed a correlation between increased MMP8 expression and rapid atherosclerotic lesion progression.11,12 A causal role of MMP8 in atherosclerosis development was demonstrated by our recent study, which showed that in apolipoprotein E (apoE)-deficient mice fed a Western diet for 12 weeks, MMP8 knockout resulted in a significant reduction of atherosclerotic lesions with decreased macrophage and VSMC contents. 13 The study also revealed a role of MMP8 in vascular recruitment of leukocytes, 13 providing a mechanistic explanation for the effect of MMP8 knockout on macrophage content in atherosclerotic lesions.In the present study, we sought to investigate whether MMP8 also plays a role in neointima formation after vessel © 2013 American Heart Association, Inc. Objective-We investigated the role of matrix metalloproteinase-8 (MMP8) in neointima formation and in vascular smooth muscle cell (VSMC) migration and proliferation. Approach and Results-After carotid artery wire injuring, MMP8-/-/apoE -/-mice had fewer proliferating cells in neointimal lesions and smaller lesion sizes. Ex vivo assays comparing VSMCs isolated from MMP8 knockout and wild-type mice showed that MMP8 knockout decreased proliferation and migration. Proteomics analysis revealed that a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) had lower concentrations in MMP8 knockout VSMC culture media than in MMP8 wild-type VSMC culture media. Western blot, flow cytometric, and immunocytochemical analyses showed that MMP8 knockout VSMCs contained more pro-ADAM10 but less mature ADAM10, more N-cadherin, and β-catenin in the plasma membrane but less β-catenin in the nucleus and less cyclin D1. Treatment of MMP8 wildtype VSMCs with an ADAM10 inhibitor, GI254023X, or siRNA knockdown of ADAM10 in MMP8 wild-type VSMCs inhibited proliferation and migration, increased N-cadherin and β-catenin in the plasma membrane, reduced β-catenin in the nucleus, and decreased cyclin D1 expression. Incubation of MMP8 knockout VSMCs with a recombinant ADAM...

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“…In addition, vinpocetine is an IKK inhibitor (Jeon et al, 2010b). IKK/nuclear factor-B signaling is implicated in smooth muscle cell proliferation and migration (Zahradka et al, 2002;Chung et al, 2009) and injury-induced neointima formation (Zuckerbraun et al, 2003;Grassia et al, 2010). Moreover, vinpocetine is a potent voltage-gated sodium channel blocker (Bönöczk et al, 2000).…”

Section: Vinpocetine Inhibits Pathological Vascular Remodeling 485mentioning

confidence: 99%

Vinpocetine Suppresses Pathological Vascular Remodeling by Inhibiting Vascular Smooth Muscle Cell Proliferation and Migration

Cai

Knight

Guo

et al. 2012

J Pharmacol Exp Ther

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Abnormal vascular smooth muscle cell (SMC) activation is associated with various vascular disorders such as atherosclerosis, in-stent restenosis, vein graft disease, and transplantationassociated vasculopathy. Vinpocetine, a derivative of the alkaloid vincamine, has long been used as a cerebral blood flow enhancer for treating cognitive impairment. However, its role in pathological vascular remodeling remains unexplored. Herein, we show that systemic administration of vinpocetine significantly reduced neointimal formation in carotid arteries after ligation injury. Vinpocetine also markedly decreased spontaneous remodeling of human saphenous vein explants in ex vivo culture. In cultured SMCs, vinpocetine dose-dependently suppressed cell proliferation and caused G 1 -phase cell cycle arrest, which is associated with a decrease in cyclin D1 and an increase in p27Kip1 levels. In addition, vinpocetine dose-dependently inhibited platelet-derived growth factor (PDGF)-stimulated SMC migration as determined by the two-dimensional migration assays and three-dimensional aortic medial explant invasive assay. Moreover, vinpocetine significantly reduced PDGF-induced type I collagen and fibronectin expression. It is noteworthy that PDGF-stimulated phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), but not protein kinase B, was specifically inhibited by vinpocetine. Vinpocetine powerfully attenuated intracellular reactive oxidative species (ROS) production, which largely mediates the inhibitory effects of vinpocetine on ERK1/2 activation and SMC growth. Taken together, our results reveal a novel function of vinpocetine in attenuating neointimal hyperplasia and pathological vascular remodeling, at least partially through suppressing ROS production and ERK1/2 activation in SMCs. Given the safety profile of vinpocetine, this study provides insight into the therapeutic potential of vinpocetine in proliferative vascular disorders.

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The IκB Kinase Inhibitor Nuclear Factor-κB Essential Modulator–Binding Domain Peptide for Inhibition of Injury-Induced Neointimal Formation

Cited by 26 publications

References 35 publications

Reduction of endoplasmic reticulum stress inhibits neointima formation after vascular injury

Reduction of endoplasmic reticulum stress inhibits neointima formation after vascular injury

Matrix Metalloproteinase-8 Promotes Vascular Smooth Muscle Cell Proliferation and Neointima Formation

Vinpocetine Suppresses Pathological Vascular Remodeling by Inhibiting Vascular Smooth Muscle Cell Proliferation and Migration

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