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Theranostics 2015; 5(3):240-250. doi:10.7150/thno.10226 This issue Cite

Research Paper

PEGylated Exendin-4, a Modified GLP-1 Analog Exhibits More Potent Cardioprotection than Its Unmodified Parent Molecule on a Dose to Dose Basis in a Murine Model of Myocardial Infarction

Zhongchan Sun^1,2*, Guang Tong^2,3*, Tae Hyung Kim², Nan Ma⁴, Gang Niu², Feng Cao^1,5✉, Xiaoyuan Chen^2✉

1. Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China 710032.
2. Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, MD 20892-2281, USA.
3. Department of Cardiovascular Surgery, General Hospital of Guangzhou Military Command, Guangzhou 510010, China;
4. Department of Ophthalmology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China;
5. Department of Cardiology, Chinese PLA General Hospital, Beijing, 100853, China.
*Zhongchan Sun and Guang Tong contributed equally to this article.

✉ Corresponding authors: Feng Cao, wind8828com; Gang Niu, gang.niugov; Xiaoyuan Chen, shawn.chengov.

Abstract

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.

Keywords: Exendin-4, PEGylation, cardioprotection, Angiogenesis, myocardial infarction.

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