Abstract
Dipeptidyl peptidase 4 inhibitors are used worldwide in the management of diabetes, but their role in the prevention or treatment of cardiovascular disorders has yet to be defined. We found that linagliptin, a DPP-4 inhibitor, suppressed capillary rarefaction in the hearts of mice with dietary obesity. Metabolomic analysis performed with capillary electrophoresis/mass spectrometry (LC-MS/MS) showed that linagliptin promoted favorable metabolic remodeling in cardiac tissue, which was characterized by high levels of citrulline and creatine. DNA microarray analysis revealed that the cardiac tissue level of early growth response protein 1 (EGR-1), which activates angiogenesis, was significantly reduced in untreated mice with dietary obesity, while this decrease was inhibited by administration of linagliptin. Mature fibroblast growth factor 2 (FGF-2) has a putative truncation site for DPP-4 at the NH2-terminal, and LC-MS/MS showed that recombinant DPP-4 protein cleaved the NH2-terminal dipeptides of mature FGF-2. Incubation of cultured neonatal rat cardiomyocytes with FGF-2 increased Egr1 expression, while it was suppressed by recombinant DPP-4 protein. Furthermore, vascular endothelial growth factor-A had a critical role in mediating FGF-2/EGR-1 signaling. In conclusion, pharmacological inhibition of DPP-4 suppressed capillary rarefaction and contributed to favorable remodeling of cardiac metabolism in mice with dietary obesity.
Highlights
Dipeptidyl peptidase 4 (DPP-4; known as CD26) is a glycoprotein that regulates a broad spectrum of biological processes through catalytic and/or non-catalytic actions [1, 2]
Systolic cardiac dysfunction and left ventricular dilatation developed in high fat diet (HFD) mice, and these changes were suppressed by linagliptin treatment (Fig 1C)
We found that dietary obesity led to capillary rarefaction and hypoxia in the cardiac tissue of HFD mice, while linagliptin treatment ameliorated these changes (Fig 1F–1I)
Summary
Dipeptidyl peptidase 4 (DPP-4; known as CD26) is a glycoprotein that regulates a broad spectrum of biological processes through catalytic and/or non-catalytic actions [1, 2]. In addition to promoting insulin secretion, GLP-1 and GIP are involved in the production of nitric oxide (NO) and atrial natriuretic peptide (ANP) [2] As well as these molecules with a critical role in the maintenance of cardiovascular homeostasis, many other biologically important mediators have putative truncation sites for DPP-4, and it is quite possible that DPP-4 is crucial for down-regulating molecules with a beneficial (and sometimes detrimental) role in cardio-metabolic disorders [3, 4]. DPP-4 inhibitor therapy slightly increased the risk of heart failure [22, 23], while other studies (including recent large-scale clinical trials) have found no additional risk [24,25,26] These conflicting results promoted us to characterize cardiac metabolism in the diabetic state with or without DPP-4 inhibitor treatment. In a murine model of dietary obesity, we found that a DPP-4 inhibitor (linagliptin) suppresses capillary rarefaction in cardiac tissue and promotes favorable metabolic remodeling, characterized by elevated levels of citrulline and creatine
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