Inhibition of dipeptidyl peptidase-4 ameliorates cardiac ischemia and systolic dysfunction by up-regulating the FGF-2/EGR-1 pathway

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.

Cardioprotection Conferred by Sitagliptin Is Associated with Reduced Cardiac Angiotensin II/Angiotensin-(1-7) Balance in Experimental Chronic Kidney Disease

“…Importantly, the data presented here show the existence of a strong positive correlation between the DPPIV activity and Ang II in the heart, while the activity of this peptidase negatively correlates with the heart levels of Ang-(1-7) (Figure 5H,I). Indeed, findings from several in vitro and ex-vivo studies demonstrate that DPPIV has direct effects on the heart [18,41,42]. Noteworthy, the DPPIV inhibitor teneligliptin prevented the pro-hypertrophic signaling induced by Ang II in isolated cardiomyocytes [18].…”

The Role of the Transcription Factor EGR1 in Cancer

“…EGR1 is important for the initiation of the growth and migration of vascular endothelial cells and associated angiogenesis because EGR1 acts via fibroblast growth factor 2 (FGF2) (46)(47)(48), which can launch EGR1 expression (49). Furthermore, EGR1 may lead to angiogenesis through the NT1-DCC-VEGF pathway (50).…”

Recent advances in capillary electrophoresis‐mass spectrometry: Instrumentation, methodology and applications

“…Rodents, rats and mice mainly, are frequently used as model organisms for basic research on metabolism. Metabolic profiling was performed on rodent muscle , heart , liver , brain , intestinal and glioma tissue, arterial cells as well as on rodent serum/plasma , urine and feces . CE‐MS was furthermore used for research on the metabolism of microorganism , plants and mushroom .…”