Strategic advantages of insulin-like growth factor-I expression for cardioprotection.
BACKGROUND
Insulin-like growth factor-I (IGF-I) peptide has beneficial effects on cardiomyocyte function and survival, many of which are mediated through the serine-threonine kinase, Akt. However, concerns about systemic effects of IGF-I peptide limit its clinical application. The present study tested whether local IGF-I expression could mediate cardioprotection without elevating serum [IGF-I].


METHODS
The ability of a recombinant adenovirus encoding IGF-IB (Ad.IGF-I) to activate Akt and protect cardiomyocytes from hypoxia-induced apoptosis in vitro was compared with the effects of IGF-I peptide or expression of constitutively active Akt (myr-Akt). In vivo, cardiac IGF-I gene transfer was performed prior to ischemia-reperfusion injury (IRI). Effects on the ischemic and infarcted areas were assessed while serum [IGF-I] was measured by radioimmunoassay.


RESULTS
Compared with IGF-I peptide, Ad.IGF-I achieved more sustained activation of Akt and reduced hypoxia-induced apoptosis at lower media IGF-I concentrations. In a co-culture system, Ad.IGF-I protected both infected and uninfected cells from hypoxic injury, while myr-Akt protected only infected cells. In vivo cardiac injection of Ad.IGF-I mediated significant local IGF-I expression, without affecting serum [IGF-I] levels. After IRI, Ad.IGF-I did not affect the ischemic area but reduced infarct size approximately 50% (32 +/- 13 vs. 64 +/- 14% AAR in Ad.GFP rats, p < 0.003), although the transgene was expressed in only approximately 15% of the ischemic region, consistent with possible paracrine benefit.


CONCLUSIONS
Somatic gene transfer of IGF-I may offer strategic advantages over both systemic delivery of IGF-I peptide and expression of cell autonomous cardioprotective transgenes such as Akt by mediating autocrine and paracrine cardiomyocyte protection without elevating serum [IGF-I] levels.
Chao
Wei
W
Program in Cardiovascular Gene Therapy, Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Matsui
Takashi
T
Novikov
Mikhail S
MS
Tao
Jingzang
J
Li
Ling
L
Liu
Heling
H
Ahn
Youngkeun
Y
Rosenzweig
Anthony
A
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D019898:Autocrine Communication; D002478:Cells, Cultured; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D019899:Paracrine Communication; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction
D011518:Proto-Oncogene Proteins; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt