The Effects Of DPP-4 Inhibitor On Hematopoietic Stem Cell Under The Chronic Stress Induction

Background:Depeptidyl peptidase4 (DPP4) inhibition protects cardiovascular injury. Hematopoietic stem cell (HSC) activation has been implicated in the pathogenesis of stress-related brain and cardiovascular diseases. Given that interaction between the psyche and the immune system provides potential mechanism linking stress and disease initiation and progression, we investigate DPP-4 inhibition-mediated immune actions in chronic stress model with a special focus on HSC activation.Objective:Given that interaction between the psyche and the immune system provides potential mechanism linking stress and disease initiation and progression, we investigate DPP-4 inhibition-related beneficial effects in chronic stress model with a special focus on hematopoietic stem cell (HSC) activation.And that DPP4 inhibition appears to improve BM HSC activation in response to chronic stress via Adrβ3/Cxcl12-dependent mechanism that is mediated GLP-1/GLP-1R axis, suggesting a novel therapeutic strategy for the management of stress-related cardiovascular disease.Method and materials:Male 8-weeks old mice underwent chronic stress (2 h twice/day; 7 days/wk) fed a normal diet were randomized assigned to 1 of 3 groups and administrated vehicle or a low or high dosage of DPP4 inhibitor anagliptin (20 or 60 mg/kg daily). Mice were left undistributed as controls. We calculated body weight (BW), systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR). We also measured the levels of plasma glucose, blood urea nitrogen (BNA), serum aspartate transaminase (AST), non-esterified fatty acid (NEFA), creatinine, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride (TG), total cholesterol (Tch), dopamine (DA), noradrenaline (NA) and adrenaline (A). ELISA was applied to evaluate the levels of plasma stromal-derived afactor-1 (SDF-1) and glucagons-like protein-1 (GLP-1). Peripheral blood was used to examine white blood cells (WBC), red blood cells (RWC), platelet, hemoglobin (Hb), mean corpuscular hemoglobin (MCV), mean corpuscular volume (MCH), neutrophils, eosinophils and monocyte. Mouse and rats bone-marrow was subjected to H&E staining and immunostaining for BrdU+, ki67+/Sca-1+, ki67+/c-kit+. We analyzed using DPPIV-GloTM Protease Assay Kit the levels of DPP4 activity in the blood as well as the tissues (including brain, muscles, liver, intestine, white adipose tissue, visceral fat, aortas, lung, and heart). Fluorescence activated cell sorting (FACS) analysis was to evaluate for mouse bone marrow:c-kit+/Sca-1+, CD48+/CD150+, Cell cycle (propedium iodide cell cycle analysis):Mouse peripheral blood:leukocyte, neutrophils, Ly6chish monocyte, Ly6clow monocyte, CD4+/CD8+, CD45+, F4/80+/Ly6C+, etc. Gelatin zymography was applied to examine the levels of matrix metalloproteinase-2 and-9 activities.In vitro, the study revealed the role of DPP4 activity contributes to HSC activation sing immunohistochemistry/immunofluorescence staining, Western blot (Western B1 ot) and other detection methods.RESULTS:As compared with control mice, the mice underwent stress had lose subcutaneous fat and inguinal fat. Consistent with the previous studies, stressed mice maintained decreased BW throughout follow-up period and had increased SBP. Plasma triglyceride was decreased and plasma NEFA as well as adrenaline and noradrenaline were increased in the stressed mice.However, there were no changes in the levels of plasma LDL, HDL, glucose, AST, BUN, and creatine between controland stress groups.1. Stress increased plasma and tissue DPP4 activity.2. Stress activated inflammatory cell production and HSC proliferation.3. DPP4 inhibition-mediated prevention of activation of HSC proliferation.4. GLP-1 agonist redressed stress-induced activation of HSC proliferation via Adrβ3/CXCL12 signaling pathway.5. DPP4 activity regulates HSC activation.Conclusions:These findings indicated that plasma DPP4 activity can serve a novel biomarker for metazoan organisms under systematic and brain organ specific stress, and that DPP4 inhibition appears to improve BM HSC activation in response to chronic stress via Adrp3/Cxcl12-dependent mechanism that is mediated GLP-1/GLP-1R axis, suggesting a novel therapeutic strategy for the management of stress-related cardiovascular disease.