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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.

SUBMITTER: Xu L

PROVIDER: S-EPMC4312211 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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

Xu Lei L Yates Cecelia C CC Lockyer Pamela P Xie Liang L Bevilacqua Ariana A He Jun J Lander Cynthia C Patterson Cam C Willis Monte M

Journal of molecular and cellular cardiology 20141001

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 hypot ...[more]

PMID: 25257914

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Project description:Background: Accumulating evidence suggests inhibiting neuroinflammation as a potential target in therapeutic or preventive strategies for Alzheimer's disease (AD). MAPK-activated protein kinase II (MK2), downstream kinase of p38 mitogen activated protein kinase (MAPK) p38 MAPK, was unveiled as a promising option for the treatment of AD. Increasing evidence points at MK2 as involved in neuroinflammatory responses. MMI-0100, a cell-penetrating peptide inhibitor of MK2, exhibits anti-inflammatory effects and is in current clinical trials for the treatment of pulmonary fibrosis. Therefore, it is important to understand the actions of MMI-0100 in neuroinflammation. Methods: The mouse memory function was evaluated using novel object recognition (NOR) and object location recognition (OLR) tasks. Brain hippocampus tissue samples were analyzed by quantitative PCR, Western blotting, and immunostaining. Near-infrared fluorescent and confocal microscopy experiments were used to detect the brain uptake and distribution after intranasal MMI-0100 application. Results: Central MMI-0100 was able to ameliorate the memory deficit induced by A?1-42 or LPS in novel object and location memory tasks. MMI-0100 suppressed LPS-induced activation of astrocytes and microglia, and dramatically decreased a series of pro-inflammatory cytokines such as TNF-?, IL-6, IL-1?, COX-2, and iNOS via inhibiting phosphorylation of MK2, but not ERK, JNK, and p38 in vivo and in vitro. Importantly, one of the reasons for the failure of macromolecular protein or peptide drugs in the treatment of AD is that they cannot cross the blood-brain barrier. Our data showed that intranasal administration of MMI-0100 significantly ameliorates the memory deficit induced by A?1-42 or LPS. Near-infrared fluorescent and confocal microscopy experiment results showed that a strong fluorescent signal, coming from mouse brains, was observed at 2 h after nasal applications of Cy7.5-MMI-0100. However, brains from control mice treated with saline or Cy7.5 alone displayed no significant signal. Conclusions: MMI-0100 attenuates A?1-42- and LPS-induced neuroinflammation and memory impairments via the MK2 signaling pathway. Meanwhile, these data suggest that the MMI-0100/MK2 system may provide a new potential target for treatment of AD.

Dataset Information

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

Publications

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

Similar Datasets

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