title: Direct injection of kit ligand-2 lentivirus improves cardiac repair and rescues mice post-myocardial infarction.
abstract: Myocardial infarction (MI) and subsequent adverse remodeling cause heart failure. Previously we demonstrated a role for Kit ligand (KL) in improving cardiac function post-MI. KL has two major isoforms; KL-1 is secreted whereas KL-2 is predominantly membrane bound. We demonstrate here first that KL-2-deficient mice have worse survival and an increased heart/bodyweight ratio post-MI compared to mice with reduced c-Kit receptor expression. Next we synthesized recombinant lentiviral vectors (LVs) that engineered functional expression of murine KL-1 and KL-2. For in vivo analyses, we directly injected these LVs into the left ventricle of membrane-bound KL-deficient Sl/Sl(d) or wild-type (WT) mice undergoing MI. Control LV/enGFP injection led to measurable reporter gene expression in hearts. Injection of LV/KL-2 attenuated adverse left ventricular remodeling and dramatically improved survival post-MI in both Sl/Sl(d) and WT mice (from 12 to 71% and 35 to 73%, respectively, versus controls). With regard toward beginning to understand the possible salutary mechanisms involved in this effect, differential staining patterns of Sca-1 and Ly49 on peripheral blood (PB) cells from therapeutically treated animals was found. Our data show that LV/KL-2 gene therapy is a promising treatment for MI.
authors.affiliation: Division of Stem Cell and Developmental Biology, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Koji
authors.initials: K
authors.lastname: Higuchi
authors.forename: Bilal
authors.initials: B
authors.lastname: Ayach
authors.forename: Takeya
authors.initials: T
authors.lastname: Sato
authors.forename: Manyin
authors.initials: M
authors.lastname: Chen
authors.forename: Sean P
authors.initials: SP
authors.lastname: Devine
authors.forename: Vanessa I
authors.initials: VI
authors.lastname: Rasaiah
authors.forename: Fayez
authors.initials: F
authors.lastname: Dawood
authors.forename: Teruyuki
authors.initials: T
authors.lastname: Yanagisawa
authors.forename: Chuwa
authors.initials: C
authors.lastname: Tei
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Takenaka
authors.forename: Peter P
authors.initials: PP
authors.lastname: Liu
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Medin
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D007267:Injections / Q000379:methods*; D016086:Lentivirus / Q000235:genetics*; D051379:Mice; D009203:Myocardial Infarction / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019089:Stem Cell Factor / Q000235:genetics* / Q000502:physiology
chemical_list: D019089:Stem Cell Factor; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins