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 longterm patency by inhibiting pathways that initiate IH. In vitro testing in human vascular smoothmuscle 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 freeMK2i-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 vascularwall smoothmuscle cells in amore contractile phenotype. These data indicate that nanoformulated MK2 inhibitors are a promising strategy for preventing graft failure.