zuki N, Kitakaze M. An interaction between glucagon-like peptide-1 and adenosine contributes to cardioprotection of a dipeptidyl peptidase 4 inhibitor from myocardial ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 308: H1287-H1297, 2015. First published March 7, 2015; doi:10.1152/ajpheart.00835.2014.-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 Ϯ 2.5% to 17.1 Ϯ 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-3␤, 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. dipeptidyl peptidase 4 inhibitor; ischemia-reperfusion injury; myocardial infarction; cardioprotection; adenosine GLUCAGON-LIKE PEPTIDE-1 (GLP-1) is mostly known as a potent antihyperglycemic hormone secreted by intestinal cells to stimulate glucose-dependent insulin secretion from pancreatic beta cells. Once in circulation, GLP-1 is rapidly metabolized by dipeptidyl peptidase 4 (DPP4). Therefore, GLP-1 analogs and DPP4 inhibitors are commonly prescribed for the treatment of diabetes mellitus (6, 11). DPP4 inhibitors also exert extrapancreatic effects in the brain, stomach, and heart (39). However, the mechanisms by which they mediate these effects remain largely unknown. Several reports showed that DPP4 inhibitors limit the infarct size after ischemia-reperfusion in the heart (15, 51), but the extent of their beneficial effects remains controversial (7,52). Recently, several reports have indicated that DPP4 forms a complex with adenosin...

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Abstract

In conclusion, the administration of 2,2,6,6-tetramethylpiperidine-1-oxyl as a RNP exerted cardioprotective effects against ischemia and reperfusion injury in canine hearts without exerting unfavorable hemodynamic effects. RNPs may represent a promising new therapy for patients with acute myocardial infarction.

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