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Physiol Rep. 2017 Mar;5(5). pii: e13152. doi: 10.14814/phy2.13152.

Inhibition of MAPK-Erk pathway in vivo attenuates aortic valve disease processes in Emilin1-deficient mouse model.

Author information

Divisions of Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Ohio.
Department of Cell Biology, Medical University of South Carolina, Charleston, South Carolina.
Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences National Institutes of Health, Bethesda, Maryland.
TriHealth Heart Institute, Cardio-Thoracic Surgery, Cincinnati, Ohio.
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Ohio
The Department of Biomedical Sciences, University of Padua, Padua, Italy.


Aortic valve disease (AVD) is a common condition with a progressive natural history, and presently, there are no pharmacologic treatment strategies. Elastic fiber fragmentation (EFF) is a hallmark of AVD, and increasing evidence implicates developmental elastic fiber assembly defects. Emilin1 is a glycoprotein necessary for elastic fiber assembly that is present in both developing and mature human and mouse aortic valves. The Emilin1-deficient mouse (Emilin1-/- ) is a model of latent AVD, characterized by activated TGFβ/MEK/p-Erk signaling and upregulated elastase activity. Emilin1-/- aortic valves demonstrate early EFF and aberrant angiogenesis followed by late neovascularization and fibrosis. The objective of this study was to test the effectiveness of three different targeted therapies. Aged (12-14 months) Emilin1-/- mice were treated with refametinib (RDEA-119, MEK1/2 inhibitor), doxycycline (elastase inhibitor), or G6-31 (anti-VEGF-A mouse antibody) for 4 weeks. Refametinib- and doxycycline-treated Emilin1-/- mice markedly reduced MEK/p-Erk activation in valve tissue. Furthermore, both refametinib and doxycycline attenuated elastolytic cathepsin K, L, MMP-2, and MMP-9 activation, and abrogated macrophage and neutrophil infiltration in Emilin1-/- aortic valves. RNAseq analysis was performed in aortic valve tissue from adult (4 months) and aged (14 months) Emilin1-/- and age-matched wild-type control mice, and demonstrated upregulation of genes associated with MAPK/MEK/p-Erk signaling and elastases at the adult stage and inflammatory pathways at the aged stage controlling for age. These results suggest that Erk1/2 signaling is an important modulator of early elastase activation, and pharmacological inhibition using refametinib may be a promising treatment to halt AVD progression.


Angiogenesis; elastases; elastic fibers; fibrosis; inflammation; valves

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