Human Erythropoietin Gene Delivery for Cardiac Remodeling of Myocardial Infarction in Rats

Background: Considerable efforts have been made to exploit cardioprotective drugs and gene delivery systems for myocardial infarction. The promising cardioprotective effects of recombinant human erythropoietin (rHuEPO) protein in animal experiments have not been consistently reproduced in clinical human trials of acute myocardial infarction; however, the molecular mechanisms underlying the inconsistent discrepancies are not yet fully understood. We hypothesized that the plasmid human erythropoietin gene (phEPO) delivered by our bioreducible polymer might produce a cardioprotective effect on post-infarct cardiac remodeling through the suppression of angiotensin II and TGF- beta . Methods and Results: We demonstrated that intramyocardial delivery of phEPO by an arginine-grafted poly (cystaminebisacrylamide-diaminohexane) (ABP) polymer in infarcted rats preserves cardiac geometry and systolic function. The reduced infarct size due to phEPO/ABP delivery was followed by a decrease in fibrosis, protection from cardiomyocyte loss, and down-regulation of apoptotic activity. In addition, the increased angiogenesis and decreased myofibroblast density in the border zone of the infarct support the beneficial effects of phEPO/ABP administration. Furthermore, phEPO/ABP delivery induced prominent suppression on Ang II and TGF- beta activity in the border zone of the infarct, interventricular septum, right ventricle, and atria. Conclusions: phEPO gene therapy delivered by a bioreducible ABP polymer for acute myocardial infarction protected against the expansion of the infarct and functional impairment, thereby attenuating adverse cardiac remodeling. These results provide insight into the lack of phEPO gene therapy translation in the treatment of heart disease to human trials.