An interaction between glucagon-like peptide-1 and adenosine contributes to cardioprotection of a dipeptidyl peptidase 4 inhibitor from myocardial ischemia-reperfusion injury.
Dipeptidyl peptidase 4 (DPP4) inhibitors suppress the metabolism of the potent antihyperglycemic hormone glucagon-like peptide-1 (GLP-1). DPP4 was recently shown to provide cardioprotection through a reduction of infarct size, but the mechanism for this remains elusive. Known interactions between DPP4 and adenosine deaminase (ADA) suggest an involvement of adenosine signaling in DPP4 inhibitor-mediated cardioprotection. We tested whether the protective mechanism of the DPP4 inhibitor alogliptin against myocardial ischemia-reperfusion injury involves GLP-1- and/or adenosine-dependent signaling in canine hearts. In anesthetized dogs, the coronary artery was occluded for 90 min followed by reperfusion for 6 h. A 4-day pretreatment with alogliptin reduced the infarct size from 43.1 ± 2.5% to 17.1 ± 5.0% without affecting collateral flow and hemodynamic parameters, indicating a potent antinecrotic effect. Alogliptin also suppressed apoptosis as demonstrated by the following analysis: 1) reduction in the Bax-to-Bcl2 ratio; 2) cytochrome c release, 3) an increase in Bad phosphorylation in the cytosolic fraction; and 4) terminal deoxynucleotidyl transferase dUTP nick end labeling assay. This DPP4 inhibitor did not affect blood ADA activity or adenosine concentrations. In contrast, the nonselective adenosine receptor blocker 8-(p-sulfophenyl)theophylline (8SPT) completely blunted the effect of alogliptin. Alogliptin did not affect Erk1/2 phosphorylation, but it did stimulate phosphorylation of Akt, glycogen synthase kinase-3β, and cAMP response element-binding protein (CREB). Only 8SPT prevented alogliptin-induced CREB phosphorylation. In conclusion, the DPP4 inhibitor alogliptin suppresses ischemia-reperfusion injury via adenosine receptor- and CREB-dependent signaling pathways.
Department of Cell Biology, National Cerebral and Cardiovascular Center, Suita, Japan;
Madoka
M
Ihara
Department of Cardiovascular Science and Technology, Kyoto Prefectural University School of Medicine, Kyoto, Japan;
Hiroshi
H
Asanuma
Department of Cell Biology, National Cerebral and Cardiovascular Center, Suita, Japan; syamazak@ncvc.go.jp.
Satoru
S
Yamazaki
Department of Medical Biochemistry, Osaka University Graduate School of Medicine, Suita, Japan;
Hisakazu
H
Kato
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan;
Yoshihiro
Y
Asano
Department of Physiological Science, Tokai University Graduate School of Medicine, Isehara, Japan;
Yoshihiro
Y
Shinozaki
Department of Physiological Science, Tokai University Graduate School of Medicine, Isehara, Japan;
Hidezo
H
Mori
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan;
Tetsuo
T
Minamino
Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Suita, Japan; and.
Masanori
M
Asakura
Department of Cardiovascular Dynamics, National Cerebral and Cardiovascular Center, Suita, Japan.
Masaru
M
Sugimachi
Department of Cell Biology, National Cerebral and Cardiovascular Center, Suita, Japan;
Naoki
N
Mochizuki
Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Suita, Japan; and.
Masafumi
M
Kitakaze
D000241:Adenosine / Q000378:metabolism*; D000243:Adenosine Deaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004285:Dogs; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006439:Hemodynamics; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058915:Purinergic P1 Receptor Antagonists / Q000494:pharmacology; D013806:Theophylline / Q000494:pharmacology; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D002316:Cardiotonic Agents; D017362:Cyclic AMP Response Element-Binding Protein; D054873:Dipeptidyl-Peptidase IV Inhibitors; D010880:Piperidines; D058915:Purinergic P1 Receptor Antagonists; D014498:Uracil; D052216:Glucagon-Like Peptide 1; D013806:Theophylline; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D018819:Dipeptidyl Peptidase 4; D000243:Adenosine Deaminase; C520853:alogliptin; D000241:Adenosine
adenosine; cardioprotection; dipeptidyl peptidase 4 inhibitor; ischemia-reperfusion injury; myocardial infarction