Direct injection of kit ligand-2 lentivirus improves cardiac repair and rescues mice post-myocardial infarction.
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.
Higuchi
Koji
K
Division of Stem Cell and Developmental Biology, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
Ayach
Bilal
B
Sato
Takeya
T
Chen
Manyin
M
Devine
Sean P
SP
Rasaiah
Vanessa I
VI
Dawood
Fayez
F
Yanagisawa
Teruyuki
T
Tei
Chuwa
C
Takenaka
Toshihiro
T
Liu
Peter P
PP
Medin
Jeffrey A
JA
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
D019089:Stem Cell Factor; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins