| Background and objective Several studies have shown that glucagon like peptide-1 (GLP-1) protects against ischemia-reperfusion injury (IRI). Liraglutide, a GLP-1 analogue, was reported to reduce infarct size and improve cardiac output in mice. (1). We planned to evaluate the effects of liraglutide on reperfusion injury in patients with acute ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). (2). IRI is directly related to the formation of reactive oxygen species (ROS), endothelial cell injury and the activation of neutrophils and platelets. Xanthine oxidase (XO) is an important source of ROS. It has been shown that xanthine dehydrogenase (XDH) to XO conversion occurs during ischemia. We planned to investigate the effects of GLP-1 on protecting cardiac microvascular endothelial cells (CMECs) from IRI through reducing the production of ROS and to elucidate the possible mechanism of this effect.Methods (1). A total of 184 patients with STEMI undergoing emergency pPCI were enrolled in this study. Of these,133 patients were randomized 1:1 to receive either liraglutide or placebo. Study treatment was commenced 30 min before intervention (1.8 mg) and maintained for 7 days after the procedure (0.6mg for 2 days,1.2mg for 2 days, followed by 1.8mg for 3 days). Cardiac magnetic resonance (CMR) imaging was used to assess the myocardial area at risk (AAR) and the final infarct size. (2). Primary cultured rat CMECs were exposed to 4 h of hypoxia (95% N2+5% CO2) and followed by 1 h of reoxygenation (95% air+5% CO2). The generation of ROS was measured by flowcytometry. XO activity was measured by biochemical assay and XO protein levels were detected by Western blot. Real-time quantitative polymerase chain reaction (RT-qPCR) can be used to qualify XDH mRNA. An annexin V/propidium iodide staining assay was used to detect cell apoptosis.Results (1). At 3 months, the primary end point, a difference in final infarct size between the two groups was -6g (95% CI-11.3 to-1.5) (P=0.05) in 84 patients evaluated with CMR. A significantly larger salvage index was found in the liraglutide group than in the placebo group (0.66±0.14 vs.0.55±0.15; P=0.001). Infarct size in relation to AAR was also smaller in the liraglutide group (0.35±0.12 vs.0.46±0.15; P<0.001). There was a tendency for a lower rate of no-reflow in liraglutide group that did not reach statistical significance (9% vs.17%, P=0.19). Left ventricular ejection fraction at 3 months was significantly different between the two groups (P<0.05). In addition, liraglutide elicited favourable changes in markers of inflammation and oxidative stress.(2). After hypoxia/reoxygenation (H/R), the production of ROS significantly increased. Endothelial XO activity and protein levels were increased after H/R. Pretreatment of with GLP-1 (10 and 20 nM/L) was capable of preventing cellular ROS increase. The GLP-1 treatment reduced H/R-induced CMECs apoptosis. GLP-1 significantly reduced XO activity and protein levels. In addition, XDH mRNA increased after H/R, GLP-1 could decrease the levels of XDH mRNA.Conclusion (1). Liraglutide could improve reperfusion injury after pPCI for STEMI, making it a potential adjuvant therapy for STEMI. (2). GLP-1 might protect CMECs from reperfusion injury through inhibiting the elevation of XO protein level and XO activity. |
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