Linagliptin improved myocardial function recovery in rat hearts after a prolonged hypothermic preservation

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Aims:To determine whether linagliptin, a dipeptidyl peptidase 4 inhibitor, can promote the recovery of cardiac function after hypothermic preservation.Main methods:Rat hearts were preserved in cold Celsior solution with or without linagliptin for 9 h. Cardiac function was evaluated at 60 min of reperfusion after hypothermic preservation. Cardiac mitochondrial morphology was observed using transmission electron microscope. The expression of dynamin-related protein 1 (Drp1), NADPH oxidase 2 (NOX2), calmodulin-dependent protein kinase II (CaMKII) were detected using Western blot.Key findings:Compared with Celsior group, supplement of Celsior solution with linagliptin (0.25–0.75 nM) could significantly prevent hypothermic preservation-induced cardiac dysfunction. The expression of NOX2 protein, ROS level and MDA content in cardium were increased after hypothermic preservation, which was inhibited by linagliptin. Although the mitofusin1, 2, optic atrophy type 1, and total Drp1 expression in myocardium did not change, the level of p-Drp1 S616 and mitochondrial Drp1 were enhanced after hypothermic preservation. Linagliptin supplement could inhibit the hypothermic preservation-induced increase in p-Drp1 S616 and mitochondrial Drp1 protein, and mitigate the mitochondrial fragmentation. Level of p-CaMKII protein enhanced after hypothermic preservation, which could be prevented by linagliptin or a NOX2 inhibitor Phox-I2. Both Phox-I2 and a CaMKII inhibitor KN-93 could reduce the hypothermic preservation-induced increase in p-Drp1 S616 and mitochondrial Drp1 protein.Significance:Supplement Celsior solution with linagliptin could improve cardiac function recovery in 9-h hypothermic preserved rat hearts. The cardioprotective effect of linagliptin might be due to the inhibition of Drp1 phosphorylation and mitochondrial translocation by preventing NOX2-mediated CaMKII activation.

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