title: 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.affiliation: Department of Cardiac Surgery, Shandong Provincial Hospital affiliated to Shandong University, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Health Promotions and Development, School of Nursing, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Cecelia C
authors.initials: CC
authors.lastname: Yates
authors.affiliation: Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Lockyer
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Ariana
authors.initials: A
authors.lastname: Bevilacqua
authors.affiliation: Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA; General Hospital of Ningxia Medical University, Yichuan, Ningxia, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: He
authors.affiliation: Moerae Matrix, 55 Madison Avenue Suite 400, Morristown, NJ 07960, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Lander
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, NC, USA; Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, NC, USA; Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA; McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.affiliation: Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA; McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA. Electronic address: monte_willis@med.unc.edu.
authors.forename: Monte
authors.initials: M
authors.lastname: Willis
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000188:drug therapy*; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology; D010455:Peptides / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000517:prevention & control; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D010455:Peptides; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C000600251:MMI-0100
keywords: Apoptosis; Cardiac ischemia; Fibrosis; MAPKAP kinase 2; MK2; MMI-0100