PET of Glucagonlike Peptide Receptor Upregulation After Myocardial Ischemia or Reperfusion Injury

Abstract

Glucagonlike peptide (GLP-1) and its receptor (GLP-1R) exhibit cardioprotective effects after myocardial ischemia and reperfusion (MI/R) in both animal studies and clinical trials. However, the kinetics of GLP-1R expression in the infarcted/ischemic myocardium has not yet been explored. The purpose of this study was to monitor the presence and time course of regional myocardial GLP-1R expression after MI/R with noninvasive PET. Methods: Male Sprague-Dawley rats underwent a 45-min transient left coronary artery occlusion, followed by reperfusion. The myocardial infarction was confirmed by electrocardiogram and cardiac ultrasound. In vivo PET was performed to determine myocardial uptake of 18 F-FBEM-Cys 40 -exendin-4 at different time points after reperfusion. The localization of 18 F-FBEM-Cys 40 -exendin-4 accumulation was determined by coregistering 18 F-FDG PET and CT images. Ex vivo autoradiography, GLP-1R immunohistochemical staining, and Western blot analysis were performed to confirm the PET results. Results: Myocardial origin and infarcted/ischemic area localization of 18 F-FBEM-Cys 40 -exendin-4 accumulation was confirmed by coregistration of small-animal CT and 18 F-FDG images. At 8 h after MI/R, tracer uptake in the infarcted/ischemic region was 0.37 6 0.05 percentage injected dose per gram, significantly higher than that in the control group (P , 0.01). The localized tracer uptake decreased, relative to the 8-h time point, but was still significantly higher than the control group on days 1 and 3 after MI/R. At 2 wk after MI/R, the tracer uptake in the affected area showed no significant difference, compared with that in the healthy myocardium. Autoradiography showed the same trend of 18 F-FBEM-Cys 40 -exendin-4 uptake in the myocardial infarcted/ischemic area. The specificity of tracer uptake into ischemic myocardium was supported by decreased tracer uptake after the rats were pretreated with an excess amount of unlabeled exendin-4. Immunohistochemical staining and Western blotting of GLP-1R protein of excised cardiac sections confirmed that the change in uptake observed by PET corresponded to a change in GLP-1R expression. Conclusion: Noninvasive PET using 18 F-FBEM-Cys 40 -exendin-4 revealed a dynamic pattern of GLP-1R upregulation in the infarcted/ischemic area after MI/R. The imaging results will deepen our understanding of the mechanism of the cardioprotective effect of GLP-1 and its analogs and potentially provide guidance for optimization of the time frame of therapeutic intervention.

Suppression of Long Non-Coding RNA LINC00652 Restores Sevoflurane-Induced Cardioprotection Against Myocardial Ischemia-Reperfusion Injury by Targeting GLP-1R Through the cAMP/PKA Pathway in Mice

“…I/R can cause additional cell death and increased infarct size, which is called I/R injury [26]. Studies have proven that lncRNA and GLP-1R are essential in myocardial I/R injury [27,28]. Therefore, our study aimed to determine the effect of lncRNA LINC00652 on myocardial I/R injury in mice with sevoflurane treatment by targeting GLP-1R through the cAMP/PKA signaling pathway.…”

“…Compared with the Sevo + I/R group, the LINC00652 expression in the myocardium of the si-LINC00652 + Sevo + I/R group further decreased, the expression of the GLP-1R and CREB proteins further increased, the infarct size further reduced, the number of apoptotic myocardial cells and inflammatory factors IL-1β and TNF-α in serum significantly decreased. A previous study showed that GLP-1 and its receptor GLP-1R exhibited cardio-protective effects after myocardial I/R in animal studies and clinical trials [28]. Several lncRNAs are dysregulated during acute myocardial infarction or heart failure, whereas others could control hypertrophy, mitochondrial function and cardiomyocyte apoptosis, and identified cardiovascular lncRNAs might play significant roles in cardiovascular diseases [36].…”

Mechanisms of Cardiovascular Injury in Type 2 Diabetes and Potential Effects of Dipeptidyl Peptidase-4 Inhibition

“…48Y53 In fact, early evidence suggests that glucagon-like peptide-1 receptor expression is upregulated in the heart in response to ischemia. 54 The cardioprotective and vasculoprotective effects of glucagon-like peptide-1 appear to be partially independent of the known glucagon-like peptide-1 receptor because neither pharmacologic blockade of the glucagonlike peptide-1 receptor signaling pathway 55 nor knockout of the glucagon-like peptide-1 receptor in mice 55 completely abolishes all of the observed effects.…”

Glucagon-like peptide-1 based therapies: Effects beyond blood glucose control

“…30 A study in rats shows regulation of the GLP-1 receptor in the heart within a few hours of experimental ischemia, that persisted for up to 3 days. 31 Sokos et al investigated the efficacy of a 5-week continuous infusion of GLP-1, in addition to standard therapy, in 12 patients with New York Heart Association class 3 and class 4 heart failure, when compared with nine control subjects. It Protective against ischaemic damage.…”