Dipeptidyl peptidase-4 inhibition prevents lung injury in mice under chronic stress via the modulation of oxidative stress and inflammation

Abstract

Exposure to chronic psychosocial stress is a risk factor for various pulmonary diseases. In view of the essential role of dipeptidyl peptidase 4 (DPP4) in animal and human lung pathobiology, we investigated the role of DPP4 in stress-related lung injury in mice.Eight-week-old male mice were randomly divided into a non-stress group and a 2-week immobilization stress group. Non-stress control mice were left undisturbed. The mice subjected to immobilized stress were randomly assigned to the vehicle or the DPP4 inhibitor anagliptin for 2 weeks. Chronic stress reduced subcutaneous and inguinal adipose volumes and increased blood DPP4 levels. The stressed mice showed increased levels in the lungs of genes and/or proteins related to oxidative stress (p67 phox , p47 phox , p22 phox and gp91 phox ), inflammation (monocyte chemoattractant protein-1, vascular cell adhesion molecule-1, and intracellular adhesion molecule-1), apoptosis (caspase-3, -8, -9), senescence (p16 INK4A , p21, and p53) and proteolysis (matrix metalloproteinase-2 to -9, cathepsin S/K, and tissue inhibitor of matrix metalloproteinase-1 and -2), and reduced levels of eNOS, Sirt1, and Bcl-2 proteins; and these effects were reversed by genetic and pharmacological inhibitions of DPP4. We then exposed human umbilical vein endothelial cells in vitro to hydrogen peroxide; anagliptin treatment was also observed to mitigate oxidative and inflammatory molecules in this setting. Anagliptin can improve lung injury in stressed mice, possibly by mitigating vascular inflammation, oxidative stress production, and proteolysis. DPP4 may become a new therapeutic target for chronic psychological stress-related lung disease in humans and animals.

Dipeptidyl peptidase‐4 disturbs adipocyte differentiation via the negative regulation of the glucagon‐like peptide‐1/adiponectin‐cathepsin K axis in mice under chronic stress conditions

“…The animal study protocols were approved by the Institutional Animal Care and Use Committees of Yanbian University and Nagoya University. Male DPP4 +/+ (C57BL/6J) and DPP4‐knockout (DPP4 −/− 30 ) mice, and male CTSK +/+ (C57BL/6J) and CTSK‐knockout (CTSK −/− 5 ) mice were used in the animal experiments; all mice were aged 8 weeks old and weighed 22–26 g. Both genotype‐matched pairs of mice were provided a growing diet and tap water ad libitum and housed three or four per cage under standard conditions (12 h light/dark cycle in a viral pathogen‐free facility) at the Animal Center of Yanbian University (for the former pair of genotype‐matched mice) and the Animal Center of Nagoya University Graduate School of Medicine (for the latter pair of genotype‐matched mice).…”

Sitagliptin ameliorates busulfan-induced pulmonary and testicular injury in rats through antioxidant, anti-inflammatory, antifibrotic, and antiapoptotic effects

“…Dipeptidyl peptidase 4 (DPP4) is an ectopeptidase bound to the cell membrane and expressed in many tissues. It has been involved in many pathways, for example, oxidative stress, inflammation, apoptosis, signal transduction, immune response regulation, and glucose metabolism 14 , 15 . Lungs are considered the second highest organ for DPP4 expression.…”

Association of the rs17574 DPP4 Polymorphism with Premature Coronary Artery Disease in Diabetic Patients: Results from the Cohort of the GEA Mexican Study

“…Membrane-anchored-form and soluble DPP4 have similar enzymatic activity [ 10 ]. Due to its broad enzymatic activity, DPP4 is not only involved in the pathogenesis of T2DM but also participates in insulin resistance, fatty liver, hypertension, and oxidative stress [ 11 , 12 , 13 , 14 ]. DPP4 also acts as a co-stimulatory molecule that participates in T-cell biology [ 15 ].…”