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    • It was reported that the expressions of DPP

    2019-12-29

    It was reported that the expressions of DPP-4 and SDF-1α increase through HIF-1α [27], [28]. Myocardial ischemia by MI enhanced the DPP-4 and SDF-1α levels in myocardium in the present study. SDF-1α is released from cardiomyocytes and has beneficial effects on cardiomyocytes through SDF-1α/CXCR4 after MI [29]. DPP-4 has 2 types of form which are membrane-bound form and soluble form. The soluble form is a result of cleavage of the membrane-bound form, but the mechanism how a cleavage of the membrane-bound form is regulated remains unknown. SDF-1α is degraded and inactivated by soluble form of DPP-4, and the beneficial effects of SDF-1α are abolished soon [30]. DPP-4 inhibition may suppress the action of DPP-4 and enhances the effects of SDF-1α on cardiomyocytes. We found that the expression level of serum DPP-4 increases in the mice after MI in the present study. Therefore, it seems that DPP-4 inhibition increases SDF-1α level by blocking the degradation of SDF-1α by DPP-4 in the mice after MI. In contrast, because the expression level of serum DPP-4 is low in the sham mice, it seems that SDF-1α level is not affected by DPP-4 in the sham mice. SDF-1α acts on cardiomyocytes through CXCR4 and activates STAT3 signaling pathways, leading to cardioprotection [31]. STAT3 has multiple biological functions including antiapoptotic effect [32]. These results suggest that the direct action of SDF-1α on the myocardium is important for the cardioprotective effects of DPP-4 inhibition after MI (Suppl. Fig. 7). We focused on cardiomyocytes to examine the effects of DPP-4 inhibition in the present study, however, DPP-4 is also reported to exist on endothelial tropisetron synthesis and fibroblasts [13]. We would like to investigate the effects of DPP-4 inhibitors on those cells in the next study. As DPP-4 inhibitors are antidiabetic drugs, the changes of metabolic aspects may be also associated with the cardioprotective effects of DPP-4 inhibitors. In the present study, we used non-diabetic mice and blood glucose levels were not changed by DPP-4 inhibitor. DPP-4 inhibitors are also reported to have an anti-inflammatory effect and it remains the possibility that DPP-4 inhibitors have indirect beneficial effects on cardiac function by inhibiting inflammation in the myocardium [33]. We are planning to investigate the relation between the anti-inflammatory effects of DPP-4 inhibitors and cardiac function in the future. And we have to elucidate the direct effects of DPP-4 inhibition on other type cells including cardiac fibroblasts and endothelial cells in the heart. The results of 3 large-scale randomized controlled trials performed to the effects of DPP-4 inhibitors on cardiovascular events in patients with diabetes were reported. Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR-TIMI 53) study randomized 16,492 patients with type 2 diabetes and a history of or at risk for cardiovascular events to saxagliptin or placebo group [34]. There was no significant difference in the primary endpoint, which was a composite of cardiovascular death, myocardial infarction, or stroke, between 2 groups for a median of 2.1years [34]. However, the risk for heart failure hospitalization was higher in the saxagliptin group than in the placebo group. Examination of Cardiovascular Outcomes with Allogliptin versus Standard of Care (EXAMINE) study randomized 5380 patients with type 2 diabetes and recent MI or unstable angina to alogliptin or placebo group [35]. There was no significant difference in the primary endpoint, which was a composite of death from cardiovascular causes, myocardial infarction, or stroke, between 2 groups for a median of 1.5years [34]. The results with regard to heart failure events were not mentioned in the paper. Recently, the result of TECOS trial was published [36]. Sitagliptin was non-inferior to placebo for the primary composite cardiovascular outcome. The composite outcome of hospitalization for heart failure or cardiovascular death occurred in 538 patients in the sitagliptin group (7.3%; 2.54 per 100person-years) and 525 in the placebo group (7.2%; 2.50 per 100person-years). Rates of hospitalization for heart failure did not differ between the two groups. We could not explain at the moment why the risk for heart failure hospitalization was high in only saxagliptin group. The detailed subanalysis of those trials and the results of further trials will clarify the issue.