Analysis of the Correlation between the Myocardial Expression of DPP-4 and the Clinical Parameters of Patients with Heart Failure.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used as antidiabetic drugs. We recently reported that DPP-4 inhibition has beneficial effects on heart failure (HF) mice model. Furthermore, we confirmed that myocardial DPP-4 activity was significantly increased in HF mice compared with non-HF mice. The aim of this study was to investigate the level of myocardial CD26 (DPP-4) expression and its association to clinical parameters in HF patients.Endomyocardial biopsy (EMB) specimens (n = 33) were obtained from HF patients who were admitted to Chiba University Hospital from June 2006 to July 2012. EMB specimens were fixed in formaldehyde and stained with Masson's trichrome staining or with anti-CD26 antibody. Patients were divided into the high CD26 density (CD26-H) or low CD26 density groups (CD26-L). DPP-4 density was compared with blood brain natriuretic peptide (BNP) level and echocardiographic parameters at one year after EMB. Although there were no significant differences in echocardiographic parameters between the CD26-H group and CD26-L group, blood BNP levels were higher in the CD26-H group than in the CD26-L group at one year after EMB. Multivariate regression analysis showed that CD26 density was also an independent determinant of blood BNP levels at one year after EMB.The level of myocardial CD26 expression might be a predictive marker of prognosis in patients with HF.

The effects of DPP-4 inhibitor on hypoxia-induced apoptosis in human umbilical vein endothelial cells.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of oral hypoglycemic agents for patients with type 2 diabetes mellitus and have potential antiatherosclerotic properties. Meanwhile, it is unclear how DPP-4 inhibitors have protective effects on atherosclerosis. Our aim was to determine the effects and its mechanisms of DPP-4 inhibitors on cultured endothelial cells. Human umbilical vein endothelial cells (HUVECs) were cultured in hypoxic condition. To evaluate the protective effects of DPP-4 inhibitor on HUVECs, DPP-4 inhibitor was added in the cell culture medium and the cell viability was assessed by TUNEL assay. And we examined the intracellular signaling pathways in relation to the effects of DPP-4 inhibitor. DPP-4 inhibition had beneficial effects by inhibiting the apoptosis under hypoxic conditions in HUVECs. The antiapoptotic effects of DPP-4 inhibitor were abolished by the pretreatment with a CXCR4 antagonist or a Stat3 inhibitor. DPP-4 inhibition has beneficial effects on HUVECs by inhibiting the apoptosis under hypoxic conditions. SDF-1α/CXCR4/Stat3 pathways might be involved in the mechanisms of the cytoprotective effects of DPP-4 inhibitor. These results suggested that DPP-4 inhibitor has a potential for protecting vessels.

Deletion of CD28 Co-stimulatory Signals Exacerbates Left Ventricular Remodeling and Increases Cardiac Rupture After Myocardial Infarction.

BACKGROUND: Inflammatory responses, especially by CD4(+)T cells activated by dendritic cells, are known to be important in the pathophysiology of cardiac repair after myocardial infarction (MI). Although co-stimulatory signals through B7 (CD80/86) and CD28 are necessary for CD4(+)T cell activation and survival, the roles of these signals in cardiac repair after MI are still unclear. METHODS AND RESULTS: C57BL/6 (Control) mice and CD28 knockout (CD28KO) mice were subjected to left coronary artery permanent ligation. The ratio of death by cardiac rupture within 5 days after MI was significantly higher in CD28KO mice compared with Control mice. Although there were no significant differences in the infarct size between the 2 groups, left ventricular end-diastolic and end-systolic diameters were significantly increased, and fractional shortening was significantly decreased in CD28KO mice compared with Control mice. Electron microscopic observation revealed that the extent of extracellular collagen fiber was significantly decreased in CD28KO mice compared with Control mice. The number of α-smooth muscle actin-positive myofibroblasts was significantly decreased, and matrix metalloproteinase-9 activity and the mRNA expression of interleukin-1ß were significantly increased in CD28KO mice compared with Control mice. CONCLUSIONS: Deletion of CD28 co-stimulatory signals exacerbates left ventricular remodeling and increases cardiac rupture after MI through prolongation of the inflammatory period and reduction of collagen fiber in the infarct scars. (Circ J 2016; 80: 1971-1979).

DPP-4 inhibition has beneficial effects on the heart after myocardial infarction.

AIMS: Dipeptidyl peptidase-4 (DPP-4) inhibitors are reported to have protective effects on various cells but it is unclear how DPP-4 inhibitors have cardioprotective effects. Our aim was to study the mechanisms of cardioprotective effects by DPP-4 inhibition. METHODS AND RESULTS: C57BL/6 mice and DPP-4 knockout (DPP-4KO) mice were subjected to left coronary artery ligation to produce acute myocardial infarction (MI). C57BL/6 mice were then treated with vehicle or DPP-4 inhibitor. Left ventricular function, infarct size, the number of vessels, and myocardial ischemia were assessed at 5days after MI. The treatment with DPP-4 inhibitor significantly improved cardiac function and decreased the infarct size. DPP-4 inhibitor increased the ratio of endothelial cell numbers to a cardiomyocyte. The extent of myocardial ischemia and the number of TUNEL-positive cells in the border area were significantly decreased by DPP-4 inhibitor. Stromal cell-derived factor-1α (SDF-1α) level in myocardium was significantly increased by DPP-4 inhibitor. Those cardioprotective effects after MI were also recognized in DPP-4KO mice. DPP-4 protein was expressed on rat neonatal cardiomyocytes and DPP-4 inhibitor significantly reduced hypoxia-induced apoptosis in the cardiomyocytes. However, this effect was abolished by the pretreatment with a CXCR4 antagonist or a signal transducer and activator of transcription 3 (STAT3) inhibitor. The beneficial effects of DPP-4 inhibitor on heart failure after MI were abolished by cardiomyocyte-specific deletion of STAT3. CONCLUSIONS: DPP-4 inhibition may have direct protective effects on the post-MI heart by inducing an antiapoptotic effect and inhibiting a decrease in vessel number through the SDF-1α/CXCR4-mediated STAT3 signaling pathway.