Dipeptidyl Peptidase‐4 Regulates Hematopoietic Stem Cell Activation in Response to Chronic Stress

Abstract

BackgroundDPP4 (Dipeptidyl peptidase‐4)‐GLP‐1 (glucagon‐like peptide‐1) and its receptor (GLP‐1R) axis has been involved in several intracellular signaling pathways. The Adrβ3 (β3‐adrenergic receptor)/CXCL12 (C‐X‐C motif chemokine 12) signal was required for the hematopoiesis. We investigated the novel molecular requirements between DPP4‐GLP‐1/GLP‐1 and Adrβ3/CXCL12 signals in bone marrow (BM) hematopoietic stem cell (HSC) activation in response to chronic stress.Methods and ResultsMale 8‐week‐old mice were subjected to 4‐week intermittent restrain stress and orally treated with vehicle or the DPP4 inhibitor anagliptin (30 mg/kg per day). Control mice were left undisturbed. The stress increased the blood and brain DPP4 levels, the plasma epinephrine and norepinephrine levels, and the BM niche cell Adrβ3 expression, and it decreased the plasma GLP‐1 levels and the brain GLP‐1R and BM CXCL12 expressions. These changes were reversed by DPP4 inhibition. The stress activated BM sca‐1highc‐Kithigh CD48low CD150high HSC proliferation, giving rise to high levels of blood leukocytes and monocytes. The stress‐activated HSC proliferation was reversed by DPP4 depletion and by GLP‐1R activation. Finally, the selective pharmacological blocking of Adrβ3 mitigated HSC activation, accompanied by an improvement of CXCL12 gene expression in BM niche cells in response to chronic stress.ConclusionsThese findings suggest that DPP4 can regulate chronic stress‐induced BM HSC activation and inflammatory cell production via an Adrβ3/CXCL12‐dependent mechanism that is mediated by the GLP‐1/GLP‐1R axis, suggesting that the DPP4 inhibition or the GLP‐1R stimulation may have applications for treating inflammatory diseases.

Chronic Psychological Stress Accelerates Vascular Senescence and Impairs Ischemia‐Induced Neovascularization: The Role of Dipeptidyl Peptidase‐4/Glucagon‐Like Peptide‐1‐Adiponectin Axis

“…We have shown that chronic stress markedly suppressed the plasma corticosterone level; this effect was restored by the treatment with anagliptin and exenatide. Recently, we have demonstrated that chronic stress also increased plasma adrenaline and noradrenaline levels, and these changes were reversed by both drugs . In addition, our observations here show that pharmacological interventions targeted toward DPP4 activity and GLP‐1R activation ameliorated the levels of plasma glucose and adipose insulin receptor substrate 1 and glucose transporter 4 genes in the stressed mice.…”

“…The luminescence intensity was calculated using a luminometer. Based on the standard curve, the plasma and tissue DPP4 levels were derived to represent as ng/mL . All measurements were performed in triplicate.…”

“…A recent study reported a close link between increased plasma DPP4 activities and inflammatory and metabolic disorders . Moreover, chronic stress increased plasma and tissue DPP4 activities in mice and rats …”

Dose rectification of an imbalance between DPP4 and GLP‐1 ameliorates chronic stress‐related vascular aging and atherosclerosis?

“…19 A recent study reported that individuals with and without diabetes mellitus had increased plasma DPP4 levels and decreased plasma GLP-1 levels. 21 In mice and rats, chronic stress increased plasma and tissue DPP4 activities and decreased plasma and brain GLP-1 levels, 22 suggesting an imbalance between DPP4 and GLP-1 as a potential therapeutic target in the management of vascular aging and atherosclerosis in animals under experimental stress conditions.…”

“…Chronic variable stress has been shown to produce harmful changes in plasma and tissue DPP4 levels. 22,23 It is established that inflammation participates in all stages of atherosclerosis, including initiation, progression, and ultimately, the thrombotic complications. 24 Data from our research and those from other groups clearly demonstrated that chronic variable stress activated bone-marrow hematopoietic stem cell proliferation via the inactivation if β-adrenergic receptor-mediated C-X-C motif chemokine 12 (CXCL12), leading to an increased output of neutrophils and inflammatory monocytes.…”