A Site-specifically PEGylated
exendin-4 (denoted as PEG-Ex4) is an
exendin-4 (denoted as Ex4) analog we developed by site-specific PEGylation of
exendin-4 with a high molecular weight trimeric poly(
ethylene glycol) (tPEG). It has been shown to possess prolonged half-life in vivo with similar receptor binding affinity compared to unmodified
exendin-4 by our previous work. This study is sought to test whether PEG-Ex4 is suitable for treating
myocardial infarction (MI). In the MI model, PEG-Ex4 was administered every 3 days while equivalent amount of Ex4 was administered every 3 days or twice daily. Animal survival rate, heart function, remodeling and neoangiogenesis were evaluated and compared. Tube formation was examined in endothelial cells. In addition, Western blotting and histology were performed to determine the markers of
cardiac hypertrophy and angiogenesis and to explore the possible molecular mechanism involved. PEG-Ex4 and Ex4 showed comparable binding affinity to
GLP-1 receptor. In MI mice, PEG-Ex4 given at 3 days interval achieved similar extent of protection as Ex4 given twice daily, while Ex4 given at 3 days interval failed to produce protection. PEG-Ex4 elevated endothelial tube formation in vitro and capillary density in the border area of MI. PEG-Ex4 increased Akt activity and
VEGF production in a GLP-1R dependent manner in endothelial cells and antagonism of GLP-1R, Akt or
VEGF abolished the protection of PEG-Ex4 in the MI model. PEG-Ex4 is a potent long-acting
GLP-1 receptor agonist for the treatment of chronic
heart disease. Its protection might be attributed to enhanced angiogenesis mediated by the activation of Akt and
VEGF.