title: MK2 inhibitory peptide delivered in nanopolyplexes prevents vascular graft intimal hyperplasia.
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.
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Evans
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Hocking
authors.affiliation: Division of Vascular Surgery, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Osgood
authors.affiliation: Division of Vascular Surgery, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Voskresensky
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Dmowska
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: Kameron V
authors.initials: KV
authors.lastname: Kilchrist
authors.affiliation: Division of Vascular Surgery, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Veterans Affairs Medical Center, VA Tennessee Valley Healthcare System, Nashville TN 37212, USA.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Brophy
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA. craig.duvall@vanderbilt.edu.
authors.forename: Craig L
authors.initials: CL
authors.lastname: Duvall
mesh_terms: D000818:Animals; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology; D053758:Nanoparticles / Q000737:chemistry*; D010455:Peptides / Q000494:pharmacology*; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011817:Rabbits; D012501:Saphenous Vein / Q000187:drug effects; D016896:Treatment Outcome; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology* / Q000601:surgery; D058017:Vascular Grafting; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D010455:Peptides; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D000099190:MAP-Kinase-Activated Kinase 2