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Publication
MK2 inhibitory peptide delivered in nanopolyplexes prevents vascular graft
intimal hyperplasia.
Authors Evans BC, Hocking KM, Osgood MJ, Voskresensky I, Dmowska J, Kilchrist KV, Brophy
CM, Duvall CL
Submitted By Submitted Externally on 10/1/2015
Status Published
Journal Science translational medicine
Year 2015
Date Published 6/1/2015
Volume : Pages 7 : 291ra95
PubMed Reference 26062847
Abstract Autologous vein grafts are commonly used for coronary and peripheral artery
bypass but have a high incidence of intimal hyperplasia (IH) and failure. We
present a nanopolyplex (NP) approach that efficiently delivers a
mitogen-activated protein kinase (MAPK)-activated protein (MAPKAP) kinase 2
inhibitory peptide (MK2i) to graft tissue to improve long-term patency by
inhibiting pathways that initiate IH. In vitro testing in human vascular smooth
muscle cells revealed that formulation into MK2i-NPs increased cell
internalization, endosomal escape, and intracellular half-life of MK2i. This
efficient delivery mechanism enabled MK2i-NPs to sustain potent inhibition of
inflammatory cytokine production and migration in vascular cells. In intact
human saphenous vein, MK2i-NPs blocked inflammatory and migratory signaling, as
confirmed by reduced phosphorylation of the posttranscriptional gene regulator
heterogeneous nuclear ribonucleoprotein A0, the transcription factor cAMP
(adenosine 3',5'-monophosphate) element-binding protein, and the chaperone heat
shock protein 27. The molecular effects of MK2i-NPs caused functional inhibition
of IH in human saphenous vein cultured ex vivo. In a rabbit vein transplant
model, a 30-min intraoperative graft treatment with MK2i-NPs significantly
reduced in vivo IH 28 days posttransplant compared with untreated or free
MK2i-treated grafts. The decrease in IH in MK2i-NP-treated grafts in the rabbit
model also corresponded with decreased cellular proliferation and maintenance of
the vascular wall smooth muscle cells in a more contractile phenotype. These
data indicate that nanoformulated MK2 inhibitors are a promising strategy for
preventing graft failure.




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