Signal peptide increases the efficacy of angiogenic gene transfer for treatment of myocardial ischemia.
We have previously shown that intracoronary delivery of recombinant adenoviruses encoding angiogenic proteins that contain signal peptides (fibroblast growth factor-4 and fibroblast growth factor-5) ameliorate myocardial ischemia. In the present paper, we test the hypothesis that the presence of the signal peptide is an important element in the favorable effects that transgene expression has on regional flow and function in an animal model of myocardial ischemia. We performed intracoronary delivery of two different recombinant adenoviruses encoding a fibroblast growth factor-2 variant, one with a signal peptide, FGF-2LI(+sp), and one without a signal peptide, FGF-2LI(-sp). In a model of stress-induced myocardial ischemia, intracoronary injection of these recombinants resulted in mRNA and protein expression of the transferred gene. Two weeks after gene transfer, regional abnormalities in stress-induced function and blood flow were improved after delivery of FGF-2LI containing the signal peptide. In the absence of the signal peptide, perfusion was not improved, and function was improved to a lesser degree than with FGF-2LI containing the signal peptide. These studies indicate that the presence of a signal peptide increases the efficacy of treatment and may reduce the required recombinant adenovirus dose for a given effect, and thereby provide an important safety margin for clinical application.
Gao
Mei Hua
MH
Veterans Administration San Diego Healthcare System, and Department of Medicine, University of California San Diego, La Jolla, CA 92161, USA.
Lai
N Chin
NC
Hammond
H Kirk
HK
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D016222:Fibroblast Growth Factor 2 / Q000235:genetics* / Q000627:therapeutic use*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D017202:Myocardial Ischemia / Q000235:genetics / Q000628:therapy*; D021382:Protein Sorting Signals / Q000235:genetics / Q000502:physiology*; D034421:Sus scrofa; D019076:Transgenes; D016896:Treatment Outcome
D021382:Protein Sorting Signals; D016222:Fibroblast Growth Factor 2