MMI-0100 inhibits cardiac fibrosis in myocardial infarction by direct actions on cardiomyocytes and fibroblasts via MK2 inhibition

Lei Xu, Cecelia C. Yates, Pamela Lockyer, Liang Xie, Ariana Bevilacqua, Jun He, Cynthia Lander, Cam Patterson, Monte Willis

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

The cell-permeant peptide inhibitor of MAPKAP kinase 2 (MK2), MMI-0100, inhibits MK2 and downstream fibrosis and inflammation. Recent studies have demonstrated that MMI-0100 reduces intimal hyperplasia in a mouse vein graft model, pulmonary fibrosis in a murine bleomycin-induced model and development of adhesions in conjunction with abdominal surgery. MK2 is critical to the pathogenesis of ischemic heart injury as MK2-/- mice are resistant to ischemic remodeling. Therefore, we tested the hypothesis that inhibiting MK2 with MMI-0100 would protect the heart after acute myocardial infarction (AMI) in vivo. AMI was induced by placing a permanent LAD coronary ligation. When MMI-0100 peptide was given 30min after permanent LAD coronary artery ligation, the resulting fibrosis was reduced/prevented ~50% at a 2week time point, with a corresponding improvement in cardiac function and decrease in left ventricular dilation. In cultured cardiomyocytes and fibroblasts, MMI-0100 inhibited MK2 to reduce cardiomyocyte caspase 3/7 activity, while enhancing primary cardiac fibroblast caspase 3/7 activity, which may explain MMI-0100's salvage of cardiac function and anti-fibrotic effects in vivo. These findings suggest that therapeutic inhibition of MK2 after acute MI, using rationally-designed cell-permeant peptides, inhibits cardiac fibrosis and maintains cardiac function by mechanisms that involve inhibiting cardiomyocyte apoptosis, while enhancing primary cardiac fibroblast cell death.

Original languageEnglish (US)
Pages (from-to)86-101
Number of pages16
JournalJournal of Molecular and Cellular Cardiology
Volume77
DOIs
StatePublished - Dec 1 2014

Keywords

  • Apoptosis
  • Cardiac ischemia
  • Fibrosis
  • MAPKAP kinase 2
  • MK2
  • MMI-0100

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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