Myocardial infarction (MI) is one of the main causes of morbidity and mortality in diabetic patients. The antidiabetic glucagon-like polypeptide-1 receptor (GLP-1R) agonists, such as exenatide, proved to confer cardioprotection; however, their exact mechanisms are not fully elucidated. Although the cardioprotective effect of α-estrogen receptor (ERα) activation is well established, its involvement in exenatide-induced cardioprotection has never been investigated. Moreover, modulation of insulin-like growth factor-1/2 (IGF-1/IGF-2) system by exenatide, and the consequent effect on cardiomyocyte apoptosis, is yet to be established. Current study aimed to investigate the cardioprotective potential of exenatide versus the standard cardioprotective agent, 17β-estradiol, against isoprenaline (ISO)-induced MI in rats. MI-insulted group showed electrocardiographic abnormalities, elevated serum cardiac markers, higher serum IGF-2 level along with histopathological abnormalities. Treatment with exenatide and/or 17β-estradiol, commenced 8 weeks before ISO insult, ameliorated these anomalies with maximum cardioprotection achieved with combined treatment. This was associated with upregulation of both ERα and IGF-1R, and downregulation of IGF-2R in left ventricles. Inhibition of ERs in Langendorff preparations confirmed their involvement in mediating exenatide-induced cardioprotective effect. Current study showed that the GLP-1R agonist exenatide exerted cardioprotection associated with upregulation of ERα and modulation of IGF-1/IGF-2 signaling in favor of antiapoptosis.
*Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt; and
†Department of Physiology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
Reprints: Mona F. El-Azab, PhD, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt (e-mail: email@example.com).
The authors report no conflicts of interest.
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A. M. Darwesh, M. F. El-Azad, and N. M. Abo-Gresha performed experiments, analyzed data, and wrote/revised the manuscript. M. F. El-Azab provided technical expertise for capturing IHC photomicrographs. N. M. Abo-Gresha provided technical expertise that was necessary for in vitro data acquisition. M. F. El-Azab critically edited the manuscript. All authors conceived the hypothesis and approved the final version of the manuscript.
Received January 18, 2017
Accepted November 10, 2017