title: Plasmid-based transient human stromal cell-derived factor-1 gene transfer improves cardiac function in chronic heart failure.
abstract: We previously demonstrated that transient stromal cell-derived factor-1 alpha (SDF-1) improved cardiac function when delivered via cell therapy in ischemic cardiomyopathy at a time remote from acute myocardial infarction (MI) rats. We hypothesized that non-viral gene transfer of naked plasmid DNA-expressing hSDF-1 could similarly improve cardiac function. To optimize plasmid delivery, we tested SDF-1 and luciferase plasmids driven by the cytomegalovirus (CMV) promoter with (pCMVe) or without (pCMV) translational enhancers or α myosin heavy chain (pMHC) promoter in a rodent model of heart failure. In vivo expression of pCMVe was 10-fold greater than pCMV and pMHC expression and continued over 30 days. We directly injected rat hearts with SDF-1 plasmid 1 month after MI and assessed heart function. At 4 weeks after plasmid injection, we observed a 35.97 and 32.65% decline in fractional shortening (FS) in control (saline) animals and pMHC-hSDF1 animals, respectively, which was sustained to 8 weeks. In contrast, we observed a significant 24.97% increase in animals injected with the pCMVe-hSDF1 vector. Immunohistochemistry of cardiac tissue revealed a significant increase in vessel density in the hSDF-1-treated animals compared with control animals. Increasing SDF-1 expression promoted angiogenesis and improved cardiac function in rats with ischemic heart failure along with evidence of scar remodeling with a trend toward decreased myocardial fibrosis. These data demonstrate that stand-alone non-viral hSDF-1 gene transfer is a strategy for improving cardiac function in ischemic cardiomyopathy.
authors.affiliation: Skirball Laboratory for Cardiovascular Cellular Therapeutics, Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sundararaman
authors.forename: T J
authors.initials: TJ
authors.lastname: Miller
authors.forename: J M
authors.initials: JM
authors.lastname: Pastore
authors.forename: M
authors.initials: M
authors.lastname: Kiedrowski
authors.forename: R
authors.initials: R
authors.lastname: Aras
authors.forename: M S
authors.initials: MS
authors.lastname: Penn
mesh_terms: D000818:Animals; D054377:Chemokine CXCL12 / Q000235:genetics*; D002908:Chronic Disease; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000378:metabolism; D006333:Heart Failure / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D009203:Myocardial Infarction / Q000628:therapy; D017202:Myocardial Ischemia / Q000628:therapy; D009206:Myocardium; D018919:Neovascularization, Physiologic; D010957:Plasmids; D011401:Promoter Regions, Genetic; D051381:Rats; D011917:Rats, Inbred Lew; D017154:Stromal Cells / Q000378:metabolism; D013997:Time Factors
chemical_list: D054377:Chemokine CXCL12