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

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 30 min after permanent LAD coronary artery ligation, the resulting fibrosis was reduced/prevented ~50% at a 2 week 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.

• Authors: Lei Xu, Cecelia C Yates, Pamela Lockyer, Liang Xie, Ariana Bevilacqua, Jun He, Cynthia Lander, Cam Patterson, Monte Willis
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 77 Pg. 86-101 (Dec 2014) ISSN: 1095-8584 [Electronic] England
• PMID: 25257914 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Intracellular Signaling Peptides and Proteins
• MMI-0100
• Peptides
• Protein Kinase Inhibitors
• MAP-kinase-activated kinase 2
• Protein Serine-Threonine Kinases

Topics

• Animals
• Apoptosis
• Cell Line
• Fibroblasts (drug effects, enzymology)
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors, metabolism)
• Mice, Inbred C57BL
• Myocardial Infarction (drug therapy)
• Myocardium (pathology)
• Myocytes, Cardiac (drug effects, enzymology)
• Peptides (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Pulmonary Fibrosis (prevention & control)