ABSTRACT
OBJECTIVES: Exenatide is a glucagon-like peptide-1 analogue that mitigates myocardial injury caused by ischemia-reperfusion injury via the survival signaling pathway. We hypothesized that exenatide would provide a protective effect in doxorubicin-induced cardiotoxicity. METHODS: H9c2 cardiomyocytes were pre-treated with exenatide followed by doxorubicin (DOX), and cell viability and intracellular reactive oxygen species (ROS) were subsequently measured. In order to determine the role of autophagy, we performed western blot as well as TUNEL and autophagosome staining. Additionally, rats were treated with exenatide 1h prior to every DOX treatment. Left ventricular (LV) function and performance were then assessed by echocardiography. Myocardial and serum ROS was measured with DHE fluorescence and ROS/RNS assay. RESULTS: DOX-induced caspase-3 activation decreased after pre-treatment with exenatide both in vivo and in vitro. Oxidative stress was attenuated by exenatide in H9c2 cells, as well as in cardiac tissue and serum. The number of autophagosomes and autophagic markers were further increased by exenatide in the DOX-treated H9c2 cells, which mediated AMPK activation. Suppression of the autophagosome abolished exenatide-induced anti-apoptotic effect. Echocardiography showed that pre-treatment with exenatide significantly improved LV dysfunction that is induced by DOX treatment. Exenatide inhibits the DOX-induced production of intracellular ROS and apoptosis in the myocardium. The autophagic markers increased in exenatide pre-treated cardiac tissue. CONCLUSION: Exenatide reduces DOX-induced apoptosis of cardiomyocytes by upregulating autophagy and improving cardiac dysfunction. These novel results highlight the therapeutic potential of exenatide to prevent doxorubicin cardiotoxicity.
Subject(s)
Apoptosis , Autophagy , Cardiotoxicity/pathology , Heart Ventricles/physiopathology , Myocardium/pathology , Oxidative Stress , Reactive Oxygen Species/metabolism , Animals , Blotting, Western , Cardiotoxicity/metabolism , Cardiotoxicity/physiopathology , Cell Line , Cell Survival , Disease Models, Animal , Doxorubicin/toxicity , Echocardiography , Heart Ventricles/diagnostic imaging , In Situ Nick-End Labeling , Male , Myocardium/metabolism , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Rats , Rats, Sprague-Dawley , Signal Transduction , Ventricular Function, LeftABSTRACT
BACKGROUND/AIMS: Atherosclerosis was reported as a clinical indicator of colorectal neoplasm. However, a direct association between colorectal neoplasm and carotid intima-media thickness (IMT), a surrogate marker for atherosclerosis, has not been established. The aim of this study was to evaluate the association between abnormal carotid IMT and colorectal neoplasm. METHODOLOGY: We reviewed the data of 192 consecutive patients who underwent both diagnostic colonoscopy and carotid IMT measurements within 3 months. The prevalence of abnormal carotid IMT was compared between patients with and without colorectal neoplasm. RESULTS: We found that the risk of abnormal IMT was 1.5 times greater in patients with colorectal adenomas and 3.5 times greater in patients with colorectal adenocarcinomas than those without colorectal neoplasms. Although the association between colorectal neoplasm and abnormal carotid IMT did not reach statistical significance, there was a statistical trend for the association between abnormal carotid IMT and colorectal adenocarcinoma by multivariate analyses (p=0.072). CONCLUSIONS: We identified a statistical trend for the association between colorectal adenocarcinoma and abnormal carotid IMT. However, further prospective studies with a greater number of participants will be necessary to confirm these findings.
