title: Inhibition of MAPK-Erk pathway in vivo attenuates aortic valve disease processes in Emilin1-deficient mouse model.
abstract: 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. TheEmilin1-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-treatedEmilin1-/-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 inEmilin1-/-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.
authors.affiliation: Divisions of Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Charu
authors.initials: C
authors.lastname: Munjal
authors.affiliation: Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Anil G
authors.initials: AG
authors.lastname: Jegga
authors.affiliation: Divisions of Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Opoka
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Ohio.
authors.forename: Ivan
authors.initials: I
authors.lastname: Stoilov
authors.affiliation: Department of Cell Biology, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Russell A
authors.initials: RA
authors.lastname: Norris
authors.affiliation: Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences National Institutes of Health, Bethesda, Maryland.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.affiliation: TriHealth Heart Institute, Cardio-Thoracic Surgery, Cincinnati, Ohio.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Smith
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Ohio bingrbh@icloud.com.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mecham
authors.affiliation: The Department of Biomedical Sciences, University of Padua, Padua, Italy.
authors.forename: Giorgio M
authors.initials: GM
authors.lastname: Bressan
authors.affiliation: Divisions of Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Hinton
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use*; D001021:Aortic Valve / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000082882:Bicuspid Aortic Valve Disease; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D018450:Disease Progression; D004318:Doxycycline / Q000494:pharmacology / Q000627:therapeutic use*; D006330:Heart Defects, Congenital / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006349:Heart Valve Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D010196:Pancreatic Elastase / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology*
chemical_list: D000906:Antibodies; D008562:Membrane Glycoproteins; C544830:N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; C030340:elastin microfibril interface located protein; D004159:Diphenylamine; D010196:Pancreatic Elastase; D004318:Doxycycline
keywords: Angiogenesis; elastases; elastic fibers; fibrosis; inflammation; valves