P354DPP4 deficiency exerts cardioprotective effect in both animal model experiments and cell studies

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Abstract

Purpose

Dipeptidyl peptidase-4 (DPP4) enzyme inhibition has been reported to increase plasma glucagon-like peptide-1 (GLP-1) level for controlling postprandial glucose concentration. Apart from the antihyperglycemic effects, DPP4 inhibitors and GLP-1 receptor agonist are discovered for the preservation of cardiovascular disease. We examined whether genetic mutation of DPP4 impact cardiac response in both animal model experiments and cell studies.

Methods

Adult Fischer 344 (wild type) and DchcHsd-DPP IV (served as DPP4 deficiency) rats were used. Cardiac function was assessed by pressure-volume loop monitoring in wild type and DPP4-deficient rats, and following coronary artery occlusion induced myocardial infarction. Plasma GLP-1 concentration and cardiac injury markers were measured. To investigate the role of GLP-1 receptor on myocardial infarction, exendin-(9-39), a GLP-1 receptor antagonist, was subcutaneously injected before coronary artery occlusion operated. Cardioprotective signaling in rat heart was examined by western blot analyses. Adult cardiomyocyte was isolated in two kinds of rats, and the effect of H2O2 induced ROS stress was performed. MTT assay (for degree of cell viability), CM-H2DCFDA staining (for endogenous reactive oxygen species detection), and TMRE staining (for detection of mitochondrial membrane potential) were executed to determine the response to H2O2.

Results

DPP4 deficiency improved functional recovery following coronary artery occlusion, with a reduction of infarct size and cardiac injury markers. Plasma GLP-1 level was upregulated in DPP4-deficient rats. Exendin-(9—39) diminished the increased phosphorylation levels of myocardial AKT, GSK-3β, and GLUT4 in post-infarcted DPP4-deficient rats. However, exendin-(9-39) did not completely abrogate the alleviation of infarct size in DPP4-deficient rats. In cell studies, DPP4-deficient cardiomyocytes were found to be resistant to H2O2. Intracellular ROS level in DPP4-deficient cardiomyocytes were found to be lower than that of in wild type cardiomyocytes after exposure to H2O2, which lead to preserve mitochondrial membrane potential and improve cell viability.

Conclusions

These findings demonstrate that DPP4 deficiency exert protective effect in both animal model experiments and cell studies, leading to improve cardiac function and enhance cell survival, which is associated with both GLP-1-dependent and -independent pathway.

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