title: 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 ± 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. wind8828@gmail.com
authors.forename: Haokao
authors.initials: H
authors.lastname: Gao
authors.forename: Dale O
authors.initials: DO
authors.lastname: Kiesewetter
authors.forename: Xiaoxiang
authors.initials: X
authors.lastname: Zhang
authors.forename: Xinglu
authors.initials: X
authors.lastname: Huang
authors.forename: Ning
authors.initials: N
authors.lastname: Guo
authors.forename: Lixin
authors.initials: L
authors.lastname: Lang
authors.forename: Naoki
authors.initials: N
authors.lastname: Hida
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Haichang
authors.initials: H
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Cao
authors.forename: Gang
authors.initials: G
authors.lastname: Niu
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D003545:Cysteine / Q000378:metabolism; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D008297:Male; D008301:Maleimides / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000378:metabolism; D049268:Positron-Emission Tomography; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation; D014688:Venoms / Q000378:metabolism
chemical_list: C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D008301:Maleimides; C512447:N-(2-(4-18F-fluorobenzamido)ethyl)maleimide; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide; D003545:Cysteine