title: Targeting extracellular DNA to deliver IGF-1 to the injured heart.
abstract: There is a great need for the development of therapeutic strategies that can target biomolecules to damaged myocardium. Necrosis of myocardium during a myocardial infarction (MI) is characterized by extracellular release of DNA, which can serve as a potential target for ischemic tissue. Hoechst, a histological stain that binds to double-stranded DNA can be conjugated to a variety of molecules. Insulin-like growth factor-1 (IGF-1), a small protein/polypeptide with a short circulating-half life is cardioprotective following MI but its clinical use is limited by poor delivery, as intra-myocardial injections have poor retention and chronic systemic presence has adverse side effects. Here, we present a novel delivery vehicle for IGF-1, via its conjugation to Hoechst for targeting infarcted tissue. Using a mouse model of ischemia-reperfusion, we demonstrate that intravenous delivery of Hoechst-IGF-1 results in activation of Akt, a downstream target of IGF-1 and protects from cardiac fibrosis and dysfunction following MI.
authors.affiliation: Division of Cardiology, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Raffay S
authors.initials: RS
authors.lastname: Khan
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia 30322, USA.
authors.forename: Mario D
authors.initials: MD
authors.lastname: Martinez
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia 30322, USA.
authors.forename: Jay C
authors.initials: JC
authors.lastname: Sy
authors.affiliation: Division of Cardiology, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Karl D
authors.initials: KD
authors.lastname: Pendergrass
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia 30322, USA.
authors.forename: Pao-lin
authors.initials: PL
authors.lastname: Che
authors.affiliation: 1] Division of Cardiology, Emory University, Atlanta, Georgia 30322, USA [2] Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia 30322, USA.
authors.forename: Milton E
authors.initials: ME
authors.lastname: Brown
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia 30322, USA.
authors.forename: E Bernadette
authors.initials: EB
authors.lastname: Cabigas
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia 30322, USA.
authors.forename: Madhuri
authors.initials: M
authors.lastname: Dasari
authors.affiliation: 1] Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia 30322, USA [2] Department of Bioengineering, University of California at Berkeley, Berkeley, CA, 94720, USA.
authors.forename: Niren
authors.initials: N
authors.lastname: Murthy
authors.affiliation: 1] Division of Cardiology, Emory University, Atlanta, Georgia 30322, USA [2] Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia 30322, USA [3] Department of Bioengineering, University of California at Berkeley, Berkeley, CA, 94720, USA [4] Emory+Children's Center for Cardiovascular Biology, Children's Healthcare of Atlanta, Atlanta, GA 30332, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Davis
mesh_terms: D000818:Animals; D002460:Cell Line; D004247:DNA / Q000378:metabolism*; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage* / Q000737:chemistry; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport
chemical_list: D007334:Insulin-Like Growth Factor I; D004247:DNA