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DPP4 deficiency preserves cardiac function via GLP-1 signaling in rats subjected to myocardial ischemia/reperfusion

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Abstract

Dipeptidyl peptidase-4 (DPP4) enzyme inhibition has been reported to increase plasma glucagon-like peptide-1 (GLP-1) level for controlling postprandial glucose concentration. Both DPP4 inhibitors and GLP-1 analog have been approved for antihyperglycemic agents. In addition to the insulinotropic effect, GLP-1 signaling was reported to modulate cardiac function. DPP4 inhibition was shown to improve survival rate after myocardial infarction in mice, but the precise mechanism remains unknown. We aimed to compare the cardiovascular responses of ischemia/reperfusion (I/R) between wild-type and DPP4-deficient rats and investigate the underlying mechanism. Rats were subjected to 45 min of coronary artery occlusion, followed by reperfusion for 2 h. Cardiac function was characterized by analyzing pressure–volume loops. As compared to wild-type rats, after I/R, DPP4-deficient rats had better cardiac performance in association with less infarct size and cardiac injury markers (LDH, ANP, and BNP), which could be attenuated by exendin-(9–39), a GLP-1 receptor antagonist. Exendin-(9–39) could diminish the increased phosphorylation levels of myocardial AKT and GSK-3β as well as the higher expression of GLUT4 in post-infarcted DPP4-deficient rats. However, exendin-(9–39) could not completely abrogate the less infarct size in DPP4-deficient rats as compared with that in wild-type rats, implicating the involvement of GLP-1 receptor-independent pathway. In summary, this study demonstrated that the benefit of cardiac protective action against I/R injury was demonstrated in DPP4-deficient rats, which is mediated through both GLP-1 receptor-dependent and receptor-independent mechanisms.

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Abbreviations

DPP4:

Dipeptidyl peptidase-4

GLP-1:

Glucagon-like peptide-1

ex(9–39):

Exendin-(9–39)

I/R:

Ischemia/reperfusion

LDH:

Lactate dehydrogenase

PKA:

Protein kinase A

PV loop:

Pressure–volume loop

GSK:

Glycogen synthase kinase

SDF-1:

Stromal cell-derived factor-1

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Acknowledgments

The authors' work was supported by the grant from the National Science Council of Taiwan, ROC (NSC 99-2323-B-002-005).

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  1. Institute of Pharmacology, College of Medicine, National Taiwan University, No.1, Sec.1, Jen-Ai Road, Taipei, 100, Taiwan

    Hui-Chun Ku, Wen-Pin Chen & Ming-Jai Su

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  1. Hui-Chun Ku
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Correspondence to Ming-Jai Su.

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Ku, HC., Chen, WP. & Su, MJ. DPP4 deficiency preserves cardiac function via GLP-1 signaling in rats subjected to myocardial ischemia/reperfusion. Naunyn-Schmiedeberg's Arch Pharmacol 384, 197–207 (2011). https://doi.org/10.1007/s00210-011-0665-3

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