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

Masayoshi Suda, Ippei Shimizu, Yohko Yoshida, Yuka Hayashi, Ryutaro Ikegami, Goro Katsuumi, Takayuki Wakasugi, Yutaka Yoshida, Shujiro Okuda, Tomoyoshi Soga, Tohru Minamino

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Article numbere0182422
JournalPLoS One
Volume12
Issue number8
DOIs
Publication statusPublished - 2017 Aug 1

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Early Growth Response Protein 1
Dipeptidyl Peptidase 4
fibroblast growth factor 2
peptidases
Fibroblast Growth Factor 2
ischemia
Ischemia
obesity
Obesity
mice
proteins
vascular endothelial growth factor A
Tissue
Dipeptidyl-Peptidase IV Inhibitors
citrulline
Capillary electrophoresis
Citrulline
creatine
Metabolomics
dipeptides

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Suda, M., Shimizu, I., Yoshida, Y., Hayashi, Y., Ikegami, R., Katsuumi, G., ... Minamino, T. (2017). Inhibition of dipeptidyl peptidase-4 ameliorates cardiac ischemia and systolic dysfunction by up-regulating the FGF-2/EGR-1 pathway. PLoS One, 12(8), [e0182422]. https://doi.org/10.1371/journal.pone.0182422

Inhibition of dipeptidyl peptidase-4 ameliorates cardiac ischemia and systolic dysfunction by up-regulating the FGF-2/EGR-1 pathway. / Suda, Masayoshi; Shimizu, Ippei; Yoshida, Yohko; Hayashi, Yuka; Ikegami, Ryutaro; Katsuumi, Goro; Wakasugi, Takayuki; Yoshida, Yutaka; Okuda, Shujiro; Soga, Tomoyoshi; Minamino, Tohru.

In: PLoS One, Vol. 12, No. 8, e0182422, 01.08.2017.

Research output: Contribution to journalArticle

Suda, M, Shimizu, I, Yoshida, Y, Hayashi, Y, Ikegami, R, Katsuumi, G, Wakasugi, T, Yoshida, Y, Okuda, S, Soga, T & Minamino, T 2017, 'Inhibition of dipeptidyl peptidase-4 ameliorates cardiac ischemia and systolic dysfunction by up-regulating the FGF-2/EGR-1 pathway', PLoS One, vol. 12, no. 8, e0182422. https://doi.org/10.1371/journal.pone.0182422
Suda, Masayoshi ; Shimizu, Ippei ; Yoshida, Yohko ; Hayashi, Yuka ; Ikegami, Ryutaro ; Katsuumi, Goro ; Wakasugi, Takayuki ; Yoshida, Yutaka ; Okuda, Shujiro ; Soga, Tomoyoshi ; Minamino, Tohru. / Inhibition of dipeptidyl peptidase-4 ameliorates cardiac ischemia and systolic dysfunction by up-regulating the FGF-2/EGR-1 pathway. In: PLoS One. 2017 ; Vol. 12, No. 8.
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