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

• Published in: Journal of molecular and cellular cardiology 2014-12, Vol.77, p.86-101
• Main Authors: Xu, Lei, Yates, Cecelia C, Lockyer, Pamela, Xie, Liang, Bevilacqua, Ariana, He, Jun, Lander, Cynthia, Patterson, Cam, Willis, Monte
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Cardiac ischemia; Cardiovascular; Cell Line; Fibroblasts - drug effects; Fibroblasts - enzymology; Fibrosis; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - metabolism; MAPKAP kinase 2; Mice, Inbred C57BL; MK2; MMI-0100; Myocardial Infarction - drug therapy; Myocardium - pathology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - enzymology; Peptides - pharmacology; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Pulmonary Fibrosis - prevention & control
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2014.09.011

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.