Coronary artery bypass grafting (CABG) with autologous human saphenous vein (HSV) is the best available treatment for severe coronary heart disease, but long-term graft patency is problematic. The per patient vein graft failure 12-18 months after CABG was 45% in the recent PREVENT IV trial (N=1,920). Vein graft failure predisposes patients to additional operations, myocardial infarction, recurrent angina, limb loss, and death. Graft failure is primarily attributable to intimal hyperplasia (IH), the process by whic vascular smooth muscle cells (VSMCs) migrate, proliferate, and deposit extracellular matrix (ECM) into a neointima that causes stenosis. We have identified MAPKAP kinase II (MK2) as a potential target for pharmacological intervention for preventing vascular graft IH. MK2 is activated directly by p38 mitogen activated kinase (MAPK), which is triggered by the mechanical and environmental stresses on the graft during transplant. Because p38 MAPK functions are diverse, p38 inhibitors cause undesirable side effects. Thus, MK2 is a logical target for inhibitin a proximal trigger of IH, and the central hypothesis of this proposal is that sustained intracellulr pharmacological inhibition of MK2 will prevent IH and improve long-term graft patency. A cell- penetrating peptidic MK2 inhibitor (MK2i) developed by project collaborators has high specificity and low toxicity, but barriers against intracellular delivery hinder its efficacy. Mechanistic studies support the notion that MK2i has promising anti-inflammatory and anti-fibrotic activity, but its potency and longevity of action are limited by internalization into and sequestration within intracellular late endosomal vesicles. To overcome the endosomal barrier, a novel polymer-based MK2i nanoplex (MK2i-NP) design has been developed in the PI's lab that improves cell internalization and endosomal escape of the MK2i peptide. Our published data verify that formulation of MK2i into endosomolytic MK2i-NPs increases peptide intracellular delivery and produces more potent and longer-lasting bioactivity relative to treatment with the free peptide. Rapid uptake and durable intracellular retention of MK2i-NPs are key criteria for this application because a brief (30 minute) treatment of the HSV tissue at the time of explant, during the period when the surgeon is preparing the site where the anastomosis will be placed, must protect the graft throughout the post-surgery healing phase. This project seeks to optimize and better elucidate the mechanism of MK2i-NPs and then to test this therapy for efficacy in inhibiting IH pathogenesis in advanced preclinical models.

Public Health Relevance

The best available treatment for many patients with severe coronary heart disease is transplantation of saphenous vein harvested from the leg into the heart where it is used to bypass blocked vessels, but 45% of patients' grafts fail within 12-18 months post-transplant. The goal of the proposed work is to develop a safe and effective nanomedicine that, following a brief treatment of the vein during the surgical procedure, will block initiation of the process (known as intimal hyperplasia) that leads to graft blockage and failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL122347-02
Application #
9247919
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Danthi, Narasimhan
Project Start
2016-04-01
Project End
2020-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
2
Fiscal Year
2017
Total Cost
$522,841
Indirect Cost
$185,349
Name
Vanderbilt University Medical Center
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
965717143
City
Nashville
State
TN
Country
United States
Zip Code
37240
Fernando, Lawrence P; Lewis, Jamal S; Evans, Brian C et al. (2018) Formulation and characterization of poly(propylacrylic acid)/poly(lactic-co-glycolic acid) blend microparticles for pH-dependent membrane disruption and cytosolic delivery. J Biomed Mater Res A 106:1022-1033
Mukalel, Alvin J; Evans, Brian C; Kilchrist, Kameron V et al. (2018) Excipients for the lyoprotection of MAPKAP kinase 2 inhibitory peptide nano-polyplexes. J Control Release 282:110-119
Yang, Lirong; Bracho-Sanchez, Evelyn; Fernando, Lawrence P et al. (2017) Poly(2-propylacrylic acid)/poly(lactic-co-glycolic acid) blend microparticles as a targeted antigen delivery system to direct either CD4+ or CD8+ T cell activation. Bioeng Transl Med 2:202-211
Wise, Eric S; Hocking, Kyle M; Evans, Brian C et al. (2017) Unregulated saphenous vein graft distension decreases tissue viscoelasticity. Perfusion 32:489-494
Kilchrist, Kameron V; Evans, Brian C; Brophy, Colleen M et al. (2016) Mechanism of Enhanced Cellular Uptake and Cytosolic Retention of MK2 Inhibitory Peptide Nano-polyplexes. Cell Mol Bioeng 9:368-381
Evans, Brian C; Hocking, Kyle M; Osgood, Michael J et al. (2015) MK2 inhibitory peptide delivered in nanopolyplexes prevents vascular graft intimal hyperplasia. Sci Transl Med 7:291ra95