Strategic advantages of insulin‐like growth factor‐I expression for cardioprotection

Abstract

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 ∼50% (32 ± 13 vs. 64 ± 14% AAR in Ad.GFP rats, p < 0.003), although the transgene was expressed in only ∼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. Copyright © 2002 John Wiley & Sons, Ltd.