Stent Thrombosis

Holmes, David R.; Kereiakes, Dean J.; Garg, Scot; Serruys, Patrick W.; Dehmer, Gregory J.; Ellis, Stephen G.; Williams, David O.; Kimura, Takeshi; Moliterno, David J.

doi:10.1016/j.jacc.2010.07.016

Cited by 359 publications

(221 citation statements)

References 80 publications

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“…25,27 As thrombosis is a common long-term complication of stent implantation, antiplatelet regimens are often prescribed to patients after stent insertion. 26 Intriguingly, rapamycin-eluting stents show reduced platelet binding and activation. 49 Our data suggests that rapamycins and other mTORC1 inhibitors may play a role in inhibiting platelet function in regions proximal to drug-eluting stents and may provide insights into future treatments for stent thrombosis.…”

Section: Discussionmentioning

confidence: 99%

“…[25][26][27] The exact mechanisms by which mTOR inhibitors act as immunosuppressants are not completely understood but may involve inhibition of peripheral blood cells with immunologic roles such as macrophages 28 and neutrophils 29 as well as platelets. 30 In this study, we investigate the role of mTOR/S6K1-mediated Rac1 activation in platelet spreading and platelet aggregation.…”

Section: Introductionmentioning

confidence: 99%

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S6K1 and mTOR regulate Rac1-driven platelet activation and aggregation

Aslan

Tormoen²,

Loren³

et al. 2011

Blood

110

105

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Platelet activation and thrombus formation are under the control of signaling systems that integrate cellular homeostasis with cytoskeletal dynamics. Here, we identify a role for the ribosome protein S6 kinase (S6K1) and its upstream regulator mTOR in the control of platelet activation and aggregate formation under shear flow. Platelet engagement of fibrinogen initiated a signaling cascade that triggered the activation of S6K1 and Rac1. Fibrinogen-induced S6K1 activation was abolished by inhibitors of Src kinases, but not Rac1 inhibitors, demonstrating that S6K1 acts upstream of Rac1. S6K1 and Rac1 interacted in a protein complex with the Rac1 GEF TIAM1 and colocalized with actin at the platelet lamellipodial edge, suggesting that S6K1 and Rac1 work together to drive platelet spreading. Pharmacologic inhibitors of mTOR and S6K1 blocked Rac1 activation and prevented platelet spreading on fibrinogen, but had no effect on Src or FAK kinase activation. mTOR inhibitors dramatically reduced collageninduced platelet aggregation and promoted the destabilization of platelet aggregates formed under shear flow conditions. Together, these results reveal novel roles for S6K1 and mTOR in the regulation of Rac1 activity and provide insights into the relationship between the pharmacology of the mTOR system and the molecular mechanisms of platelet activation. (Blood. 2011;118(11):3129-3136) IntroductionPlatelets represent a specialized set of peripheral blood cells that are optimally configured for adhesion, secretion and aggregation at sites of vascular injury. 1,2 The exposure of platelets to extracellular matrix proteins such as collagen or laminin, or endogenous agonists such as ADP or thromboxanes, mediates hemostasis by activating signaling pathways that ultimately result in platelet adhesion and aggregation. 3 On the engagement of the adhesive proteins fibrinogen and fibronectin, platelet tyrosine kinases such as Src, Syk and FAK are recruited to the platelet cytosolic cell surface to initiate signaling pathways to drive platelet cytoskeletal reorganization through the Rho family small GTPase Rac1. [3][4][5] Rac1 regulates actin polymerization at the cell membrane to drive the growth and extension of platelet lamellipodiae that form the basis for platelet spreading. 4 The molecular mechanisms by which tyrosine kinases ultimately activate Rac1 remain ill-defined.The 70 kDa ribosome S6 protein kinase (S6K1) regulates the ribosome S6 protein to integrate processes of protein translation with cell growth and cell proliferation. 6 In cultured cells as well as in vivo, mitogenic signals triggered by nutrients and growth factors initiate a complex sequence of signaling events to activate the mammalian target of rapamycin (mTOR), a serine/threonine kinase which regulates S6K1 phosphorylation and activation. 7 Treatment of cells with rapamycin (Sirolimus) or other inhibitors of mTOR blocks S6K1 Thr389 phosphorylation and inhibits S6K1 activation. 8 The ability of mTOR inhibitors to arrest the growth of transformed tumor cells with...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

S6K1 and mTOR regulate Rac1-driven platelet activation and aggregation

Aslan

Tormoen²,

Loren³

et al. 2011

Blood

110

105

View full text Add to dashboard Cite

show abstract

“…Stent thrombosis, which is a rare but serious complication of treatment with both bare-metal stents and drug-eluting stents, 25 has been related to procedural factors and inadequate platelet inhibition during the early postimplantation period, as well as to chronic inflammation and delayed arterial healing during late follow-up. 25 Early studies used different definitions of stent thrombosis, making comparisons across reports challenging.…”

Section: Stent Thrombosismentioning

confidence: 99%

Drug-Eluting Coronary-Artery Stents

2013

N Engl J Med

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“…The restenosis rate has been substantially decreased by the use of bare metal stents (BMS) [3], particularly with the use of drug-eluting stents (DES) [4]; however, DES may cause late stent thrombosis, one of the major DES-linked complications [5,6,7]. A number of causes, including lack of antiplatelet therapy [8] and dysfunctional endothelium [9], potentially contribute to late stent thrombosis.…”

mentioning

confidence: 99%

A new rapamycin-abluminally coated chitosan/heparin stent system accelerates early re-endothelialisation and improves anti-coagulant properties in porcine coronary artery models

Gao¹,

Zheng²,

Jin³

et al. 2014

CIM

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A new rapamycin-abluminally coated chitosan/heparin stent system accelerates early re-endothelialisation and improves anti-coagulant properties in porcine coronary artery models Abstract Purpose: Drug-eluting stents (DES) in percutaneous coronary intervention are more effective in preventing in-stent restenosis compared with bare metal stents (BMS); however, DES may cause late stent thrombosis, which has limited its use. In this study, the functional properties of a newly developed DES (RAP/CS/HEP), in which rapamycin was abluminally-loaded onto a chitosan/heparin coating stent (CS/HEP), were investigated in large animal artery injury models. Methods:The effectiveness of BMS, RAP (the traditional version of rapamycin DES), CS/HEP and RAP/CS/HEP stents in preventing coagulation and promoting reendothelialisation was examined and compared in the porcine coronary artery models with arteriovenous shunt, high load thrombus and coronary balloon injury at day 7 and 28, respectively, after stent implantation. The re-endothelialisation on these stents was further evaluated in terms of endothelial gene expression using quantitative RT-PCR.Results: In the porcine coronary artery injury models, both RAP and RAP/CS/HEP stents were potent in reducing neointimal thickness, thus enlarging lumen area efficiently in the stented artery region compared with BMS and CS/HEP. RAP/CS/HEP stents facilitated re-endothelialisation and inhibited thrombosis more efficiently than BMS and RAP. Consistent with this, the expression of endothelial genes, such as CD31, CD34, eNOS and VEGF, was significantly elevated with RAP/CS/HEP stents compared with RAP and BMS stents. Conclusion:Abluminal coating of rapamycin onto the endothelialisation-accelerated CS/ HEP stent and may prove to be an efficient treatment for tackling the late stent thrombosis associated with the traditionally circumferential RAP stent. This new RAP/CS/HEP stent system exhibits considerably improved therapeutic activity.

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Stent Thrombosis

Cited by 359 publications

References 80 publications

S6K1 and mTOR regulate Rac1-driven platelet activation and aggregation

S6K1 and mTOR regulate Rac1-driven platelet activation and aggregation

Drug-Eluting Coronary-Artery Stents

A new rapamycin-abluminally coated chitosan/heparin stent system accelerates early re-endothelialisation and improves anti-coagulant properties in porcine coronary artery models

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