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

Vascul Pharmacol. Jan-Feb 2012;56(1-2):47-55. doi: 10.1016/j.vph.2011.07.008. Epub 2011 Oct 17.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Endothelial Cells / drug effects
  • Endothelial Cells / enzymology
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Fibrosis / drug therapy
  • Fibrosis / metabolism
  • Fibrosis / pathology
  • Graft Occlusion, Vascular / drug therapy
  • Graft Occlusion, Vascular / metabolism
  • Graft Occlusion, Vascular / pathology
  • Humans
  • Hyperplasia / drug therapy*
  • Hyperplasia / enzymology
  • Hyperplasia / metabolism
  • Hyperplasia / pathology
  • Interleukin-6 / antagonists & inhibitors
  • Interleukin-6 / metabolism
  • Interleukin-8 / metabolism
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Molecular Sequence Data
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / pathology
  • Nitroprusside / pharmacology
  • Peptides / pharmacology*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism
  • Saphenous Vein / drug effects
  • Saphenous Vein / physiology
  • Tunica Intima / drug effects*
  • Tunica Intima / enzymology
  • Tunica Intima / metabolism
  • Tunica Intima / pathology
  • Vasodilation / drug effects
  • Vasodilation / physiology

Substances

  • Anti-Inflammatory Agents
  • IL6 protein, human
  • Interleukin-6
  • Interleukin-8
  • Intracellular Signaling Peptides and Proteins
  • Peptides
  • Protein Kinase Inhibitors
  • Nitroprusside
  • MAP-kinase-activated kinase 2
  • Protein-Serine-Threonine Kinases