Topical Mitogen-Activated Protein Kinases Inhibition Reduces Intimal Hyperplasia in Arterialized Vein Grafts

Gulkarov, Iosif; Bohmann, Katja; Cinnante, Karma M.; Pirelli, Luigi; Yu, Pey‐Jen; Grau, Juan B.; Pintucci, Giuseppe; Galloway, Aubrey C.; Mignatti, Paolo

doi:10.1016/j.jss.2008.04.025

Cited by 8 publications

(6 citation statements)

References 32 publications

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“…It also suggests the likelihood of even greater efficacy using more potent inhibitors and approaches to established or new targets. Recent studies have shown that topical pretreatment of vein grafts with the ERK1/2 inhibitor UO126 effectively reduces neointimal formation after vein graft arterialization (40). Local delivery of c-Jun-targeting agents, alone, or in combination with other strategies, provides a new opportunity to improve vein graft patency following coronary artery or peripheral vascular bypass surgery.…”

Section: Discussionmentioning

confidence: 99%

c-Jun Regulates Shear- and Injury-inducible Egr-1 Expression, Vein Graft Stenosis after Autologous End-to-Side Transplantation in Rabbits, and Intimal Hyperplasia in Human Saphenous Veins

Waldman

Khachigian

2010

Journal of Biological Chemistry

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Coronary artery bypass graft failure represents an unsolved problem in interventional cardiology and heart surgery. Late occlusion of autologous saphenous vein bypass grafts is a consequence of neointima formation underpinned by smooth muscle cell (SMC) migration and proliferation. Poor long term patency and the lack of pharmacologic agents that prevent graft failure necessitate effective alternative therapies.

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Section: Discussionmentioning

confidence: 99%

c-Jun Regulates Shear- and Injury-inducible Egr-1 Expression, Vein Graft Stenosis after Autologous End-to-Side Transplantation in Rabbits, and Intimal Hyperplasia in Human Saphenous Veins

Waldman

Khachigian

2010

Journal of Biological Chemistry

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“…In an attempt to identify more cell-type-specific agents with fewer negative endothelial effects, we screened for drugs that reduce intimal hyperplasia by forcing differentiation of proliferative synthetic SMCs to a more mature, less proliferative contractile state. Interestingly, three compounds identified in our screen, UO126, Y27632, and retinoic acid, have all been shown to inhibit intimal hyperplasia in previous studies (DeRose et al., 1999, Gulkarov et al., 2009, Sawada et al., 2000); validating this as a suitable method for identifying inhibitors of intimal hyperplasia. Importantly, RepSox was identified in our assay as the most potent inducer of the contractile state, having not been described previously as such.…”

Section: Discussionsupporting

confidence: 69%

“…Therefore, we hypothesized that screening for molecules that drive ESC differentiation to a mature, contractile SMC phenotype might also block the dedifferentiation and restore the contractile phenotype of primary SMCs, and that such molecules might prove useful for inhibiting intimal hyperplasia in vivo . Indeed, among the molecules identified in our screen (Figure 1C) UO126, Y27632, and retinoic acid have all been shown to inhibit neointimal hyperplasia previously (DeRose et al., 1999, Gulkarov et al., 2009, Sawada et al., 2000).…”

Section: Resultsmentioning

confidence: 70%

A Human Pluripotent Stem Cell-Based Screen for Smooth Muscle Cell Differentiation and Maturation Identifies Inhibitors of Intimal Hyperplasia

et al. 2019

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Contractile to synthetic phenotypic switching of smooth muscle cells (SMCs) contributes to stenosis in vascular disease and vascular transplants. To generate more contractile SMCs, we performed a high-throughput differentiation screen using a MYH11-NLuc-tdTomato human embryonic stem cell reporter cell line. We identified RepSox as a factor that promotes differentiation of MYH11-positive cells by promoting NOTCH signaling. RepSox induces SMCs to exhibit a more contractile phenotype than SMCs generated using PDGF-BB and TGF-b1, two factors previously used for SMC differentiation but which also cause intimal hyperplasia. In addition, RepSox inhibited intimal hyperplasia caused by contractile to synthetic phenotypic switching of SMCs in a rat balloon injury model. Thus, in addition to providing more contractile SMCs that could prove useful for constructing artificial blood vessels, this study suggests a strategy for identifying drugs for inhibiting intimal hyperplasia that act by driving contractile differentiation rather than inhibiting proliferation non-specifically.

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“…In a canine model of external jugular vein interposition in the carotid artery, it was suggested that MAPK pathway activation is bimodal, as p38 activation was noted rapidly (between 30 min and 3 h) after surgery and later (4 days), which, at a later timepoint, was associated with VSMC activation [77] . Topical MAPK inhibitors significantly suppressed graft disease in a rabbit inter-positional model of vein grafting [78] , although not cell-specific, this provides further evidence for the role of MAPK in vein graft failure. Moreover, pharmacological vasorelaxation suppressed p38 activity and restricted the activation of proliferation and cell cycle progression in the porcine carotid jugular interposition graft [79] .…”

Section: Intimal Hyperplasia and The Endotheliummentioning

confidence: 63%

Activation and inflammation of the venous endothelium in vein graft disease

et al. 2017

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The long saphenous vein is the most commonly used conduit in coronary artery bypass graft (CABG) surgery when bypassing multiple diseased arteries; however, its use is complicated by the development of vascular inflammation, intimal hyperplasia and accelerated atherosclerosis leading to compromised graft efficacy. Despite refinement of surgical techniques to improve graft patency, late vein graft failure remains a significant problem. Moreover, there is a lack of pharmacological interventions proven to be effective in the treatment of late vein graft failure. A greater understanding of the molecular nature of the disease and the interactions between endothelial and smooth muscle cells as a result of alterations in local haemodynamics may assist with designing future beneficial pharmacological interventions. Venous endothelial cells (ECs) are physiologically adapted to chronic low shear stress; however, once the graft is implanted into the arterial circulation, they become suddenly exposed to acute high levels of shear stress. A small number of in vitro and ex vivo studies have demonstrated that acute high shear stress is associated with the activation of a pro-inflammatory profile in saphenous vein ECs, which may be mediated by mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signalling pathways. The impact of acute changes in shear stress on venous ECs and the role of ECs in the development of intimal hyperplasia remains incomplete and is the subject of this review.

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Topical Mitogen-Activated Protein Kinases Inhibition Reduces Intimal Hyperplasia in Arterialized Vein Grafts

Cited by 8 publications

References 32 publications

c-Jun Regulates Shear- and Injury-inducible Egr-1 Expression, Vein Graft Stenosis after Autologous End-to-Side Transplantation in Rabbits, and Intimal Hyperplasia in Human Saphenous Veins

c-Jun Regulates Shear- and Injury-inducible Egr-1 Expression, Vein Graft Stenosis after Autologous End-to-Side Transplantation in Rabbits, and Intimal Hyperplasia in Human Saphenous Veins

A Human Pluripotent Stem Cell-Based Screen for Smooth Muscle Cell Differentiation and Maturation Identifies Inhibitors of Intimal Hyperplasia

Activation and inflammation of the venous endothelium in vein graft disease

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