Inhibition of Mitogen Activated Protein Kinase Activated Protein Kinase II with MMI-0100 reduces intimal hyperplasia ex vivo and in vivo.
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.
Department of Surgery, Yale University School of Medicine, New Haven, CT, USA.
Akihito
A
Muto
Alyssa
A
Panitch
Namho
N
Kim
Kinam
K
Park
Padmini
P
Komalavilas
Colleen M
CM
Brophy
Alan
A
Dardik
D000595:Amino Acid Sequence; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006083:Graft Occlusion, Vascular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006965:Hyperplasia / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009599:Nitroprusside / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012501:Saphenous Vein / Q000187:drug effects / Q000502:physiology; D017539:Tunica Intima / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D000099190:MAP-Kinase-Activated Kinase 2; D000093242:Interleukin-6 Inhibitors
D000893:Anti-Inflammatory Agents; D015850:Interleukin-6; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; D009599:Nitroprusside; D010455:Peptides; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D000099190:MAP-Kinase-Activated Kinase 2; D000093242:Interleukin-6 Inhibitors; C508600:IL6 protein, human