br Authors contribution br Disclosure

Authors contribution
Disclosure statement
Acknowledgements This study has received funding from the Italian Ministry of University and Research (PRIN 2015, grant number 2015373Z39_008) and from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115797 (INNODIA) (this Joint Undertaking receives support from the Union\'s Horizon 2020 research and innovation programme and “EFPIA”, ‘JDRF” and “The Leona M. and Harry B. Helmsley Charitable Trust”), and from the European Union Project T2DSystems in the Horizon 2020 Programme of the European Commission, grant number H2020-PHC-02-2015.
Introduction Recent medical advances have improved survival rates of patients with acute myocardial infarction (MI), but the number of patients showing heart failure after MI has recently been increasing [1]. Left ventricular (LV) remodeling, which includes dilatation of the ventricle and increased interstitial fibrosis, is the critical process that underlies the progression to heart failure after MI [2]. Although recent pharmacological therapies are effective, heart failure is still one of the leading causes of death worldwide [3], [4]. Therefore, it is important to elucidate a novel approach to prevent LV remodeling and heart failure after MI. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of antidiabetic drugs that block DPP-4 enzyme activity [5]. As DPP-4 degrades and inactivates incretin hormones such as glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP), DPP-4 inhibitors lower blood glucose level. Many basic researches reported that DPP-4 inhibitors have protective effects on various organ including pancreas, kidney, and heart [6]. There are several papers that demonstrate the cardioprotective effects of DPP-4 inhibitors [7], [8], [9], [10]. Those papers report that DPP-4 inhibitors-induced increases in GLP-1 and stromal cell-derived factor-1α (SDF-1α), which is also a substrate of DPP-4 and produces its effects through its receptor CXCR4 [11], contribute to the protective effects of DPP-4 inhibitors. Antiapoptotic effect and angiogenesis are recognized in the hearts treated by DPP-4 inhibitors [12]. Interestingly, Zaruba et al. reported that DPP-4 inhibition in combination with granulocyte colony-stimulating factor (G-CSF) increased myocardial homing of CXCR4+ epinastine hydrochloride through an increase in SDF-1α activity and improved cardiac function after MI [13].
Materials and methods
Results
Discussion It is important to elucidate a novel approach to prevent LV remodeling and heart failure after MI because the number of patients with acute MI has been increasing. Although recent pharmacological therapies including renin-angiotensin system inhibitors and β blockers have evidence to reduce cardiovascular events in patients with heart failure, the effects of pharmacotherapies are not yet enough to treat the patients. We and other groups demonstrated that G-CSF and erythropoietin (EPO) have beneficial effects on post-MI hearts [2], [21], [22]. G-CSF has antiapoptotic effect on cardiomyocytes through Jak2/STAT3 signaling pathways [21], whereas EPO induces angiogenesis through sonic hedgehog signaling pathways in cardiomyocytes [2]. Novel drugs which have antiapoptotic effect and induce angiogenesis are expected to prevent LV remodeling and heart failure after MI powerfully. DPP-4 inhibitors are newly available drugs for diabetes mellitus [23]. DPP-4 is a serine protease which cleaves a dipeptide from the N-terminus of incretin. It has been reported that DPP-4 degrades and inactivates many other substrates other than incretin. Interestingly, G-CSF and EPO, which have cardioprotective effects as mentioned above, are also reported to be substrates of DPP-4 [24]. There are several papers that demonstrate the cardioprotective effects of DPP-4 inhibitors [13], [25]. Those papers suggest that there are possibilities that GLP-1 and SDF-1α contribute to the protective effects of DPP-4 inhibitors. Although GLP-1 was reported to have beneficial effects on heart failure through survival signaling pathways [26], the dose of GLP-1 administered in those studies was very high. DPP-4 inhibitor increased the serum GLP-1 concentration after MI, but the levels of GLP-1 were quite low in all groups in the present study. It was reported that SDF-1α increased by DPP-4 inhibitor induces mobilization of bone marrow stem cells and differentiation into vessels, resulting in improvement of cardiac function [19]. As we evaluated hearts at 5days after MI that is short period to accomplish angiogenesis in the hearts, we do not think there is a possibility that angiogenesis induced by SDF-1α is associated with DPP-4 inhibitor-induced improvement of cardiac function. Although we did not examine DPP-4-induced homing of stem cell in myocardium at 5days after MI, DPP-4 inhibitor did not increase the number of Ki67-positive endothelial cells in the myocardium at 5days after MI. However, we have to investigate the mechanisms of DPP-4 inhibition on post-MI hearts in the long term effect (e.g. 28days after MI) to exclude the possibility in the future.