Inhibition of Mitogen Activated Protein Kinase Activated Protein Kinase II with MMI-0100 reduces intimal hyperplasia ex vivo and in vivo.

Muto A, Panitch A, Kim N, Park K, Komalavilas P, Brophy CM, Dardik A
Vascul Pharmacol. 2012 56 (1-2): 47-55

PMID: 22024359 · PMCID: PMC3268886 · DOI:10.1016/j.vph.2011.07.008

Vein graft intimal hyperplasia remains the leading cause of graft failure, despite many pharmacological approaches that have failed to translate to human therapy. We investigated whether local suppression of inflammation and fibrosis with MMI-0100, a novel peptide inhibitor of Mitogen Activated Protein Kinase Activated Protein Kinase II (MK2), would be an alternative strategy to reduce cell proliferation and intimal hyperplasia. The cell permeant peptide MMI-0100 was synthesized using standard Fmoc chemistry. Pharmacological doses of MMI-0100 induced minimal human endothelial and smooth muscle cell proliferation (30% and 12% respectively). MMI-0100 suppressed IL-6 expression to control levels, without effect on IL-8 expression. MMI-0100 caused sodium nitroprusside induced smooth muscle cell relaxation and inhibited intimal thickening in human saphenous vein rings in a dose-dependent fashion. In a murine aortic bypass model, MMI-0100 reduced intimal thickness in vein grafts by 72%, and there were fewer F4/80-reactive cells in vein grafts treated with MMI-0100. MMI-0100 prevents vein graft intimal thickening ex vivo and in vivo. These results suggest that inhibition of MK2 with the cell-permeant peptide MMI-0100 may be a novel strategy to suppress fibrotic processes such as vein graft disease.

Published by Elsevier Inc.

MeSH Terms (23)

Amino Acid Sequence Animals Anti-Inflammatory Agents Cell Proliferation Cells, Cultured Endothelial Cells Fibrosis Graft Occlusion, Vascular Humans Hyperplasia Interleukin-6 Interleukin-8 Intracellular Signaling Peptides and Proteins Mice Molecular Sequence Data Myocytes, Smooth Muscle Nitroprusside Peptides Protein-Serine-Threonine Kinases Protein Kinase Inhibitors Saphenous Vein Tunica Intima Vasodilation

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