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

doi: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

PLoS One. 2017 Aug 3;12(8):e0182422. doi: 10.1371/journal.pone.0182422. eCollection 2017.

Authors

Affiliations

¹ Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
² Division of Molecular Aging and Cell Biology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
³ Department of Structural Pathology, Institute of Nephrology, Graduate School of Medical and Dental Sciences, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
⁴ Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
⁵ Institute for Advanced Biosciences, Keio University, Yamagata, Japan.

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.

MeSH terms

Amino Acid Sequence
Animals
Cells, Cultured
Dipeptidyl Peptidase 4 / chemistry*
Dipeptidyl Peptidase 4 / metabolism
Dipeptidyl-Peptidase IV Inhibitors / pharmacology
Early Growth Response Protein 1 / metabolism*
Fibroblast Growth Factor 2 / metabolism*
Gene Expression Regulation / drug effects
Heart Diseases / etiology
Heart Diseases / metabolism
Heart Diseases / prevention & control*
Linagliptin / pharmacology*
Male
Mice
Mice, Inbred C57BL
Myocardial Ischemia / etiology
Myocardial Ischemia / metabolism
Myocardial Ischemia / prevention & control*
Obesity / complications
Rats
Rats, Wistar
Sequence Homology
Systole / drug effects*

Substances

Dipeptidyl-Peptidase IV Inhibitors
Early Growth Response Protein 1
Fibroblast Growth Factor 2
Linagliptin
Dipeptidyl Peptidase 4

Grants and funding

This work was supported by a Grant-in-Aid for Scientific Research (Grant number 17H04172), a Grant-in-Aid for Scientific Research on Innovative Areas (Stem Cell Aging and Disease, Grant number 26115008), a Grant-in-Aid for Exploratory Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT, Grant number 15K15306) of Japan, grants from the Takeda Medical Research Foundation, the Japan Foundation for Applied Enzymology, the Takeda Science Foundation, the SENSHIN Medical Research Foundation, the Terumo Foundation, the Manpei Suzuki Diabetes Foundation, the Naito Foundation, and the NOVARITIS foundation, and the consigned research fund from Boehringer Ingelheim, Inc. (to T.M.) as well as by a Grants-in-Aid for Young Scientists (Start-up) (JSPS KAKENHI, Grant Number 26893080), and grants from the Uehara Memorial Foundation, Takeda Science Foundation, Kowa Life Science Foundation, Manpei Suzuki Diabetes Foundation, Kanae Foundation, Japan Heart Foundation Research Grant, The Senri Life Science Foundation, SENSHIN Medical Research Foundation, ONO Medical Research Foundation, Tsukada Grant for Niigata University Medical Research, The Nakajima Foundation, SUZUKEN memorial foundation, Inamori Foundation, Mochida Memorial Foundation for Medical & Pharmaceutical Research, MSD Life Science Foundation, Public Interest Incorporated Foundation, Grant for Basic Science Research Projects from The Sumitomo Foundation, Grants-in-Aid for Encouragement of Young Scientists (A) (JSPS KAKENHI Grant Number 16H06244), Grant From Japan Cardiovascular Research Foundation, Japan Diabetes Foundation, Kimura Memorial Heart Foundation, TERUMO FOUNDATION for LIFE SCIENCES and ARTS (to I.S.); by a Grants-in-Aid for Encouragement of Young Scientists (B) (JSPS KAKENHI Grant Number 16K19531), a Japan Heart Foundation Dr. Hiroshi Irisawa & Dr. Aya Irisawa Memorial Research Grant, Senshin Medical Research Foundation grant, SUZUKEN memorial foundation, Takeda Science Foundation, ONO Medical Research Foundation, Uehara Memorial Foundation, Research Foundation for Community Medicine, Kanae Foundation, Banyu Foundation Research Grant (to Y.Y.) and by a grant from Bourbon (to T.M., I.S. and Y.Y.). All the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Boehringer Ingelheim supplied the DPP4 inhibitor, but was not involved in study design, data collection and analysis, decision to publish, or preparation of the manuscript.