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.

Exposure to chronic psychosocial stress is a risk factor for metabolic disorders. Because dipeptidyl peptidase-4 (DPP4) and cysteinyl cathepsin K (CTSK) play important roles in human pathobiology, we investigated the role(s) of DPP4 in stress-related adipocyte differentiation, with a focus on the glucagon-like peptide-1 (GLP-1)/adiponectin-CTSK axis in vivo and in vitro. Plasma and inguinal adipose tissue from non-stress wild-type (DPP4+/+), DPP4-knockout (DPP4-/-) and CTSK-knockout (CTSK-/-) mice, and stressed DPP4+/+, DPP4-/-, CTSK-/-, and DPP4+/+ mice underwent stress exposure plus GLP-1 receptor agonist exenatide loading for 2 weeks and then were analyzed for stress-related biological and/or morphological alterations. On day 14 under chronic stress, stress decreased the weights of adipose tissue and resulted in harmful changes in the plasma levels of DPP4, GLP-1, CTSK, adiponectin, and tumor necrosis factor-α proteins and the adipose tissue levels of CTSK, preadipocyte factor-1, fatty acid binding protein-4, CCAAT/enhancer binding protein-α, GLP-1 receptor, peroxisome proliferator-activated receptor-γ, perilipin2, secreted frizzled-related protein-4, Wnt5α, Wnt11 and ß-catenin proteins and/or mRNAs as well as macrophage infiltration in adipose tissue; these changes were rectified by DPP4 deletion. GLP-1 receptor activation and CTSK deletion mimic the adipose benefits of DPP4 deficiency. In vitro, CTSK silencing and overexpression respectively prevented and facilitated stress serum and oxidative stress-induced adipocyte differentiation accompanied with changes in the levels of pref-1, C/EBP-α, and PPAR-γ in 3T3-L1 cells. Thus, these findings indicated that increased DPP4 plays an essential role in stress-related adipocyte differentiation, possibly through a negative regulation of GLP-1/adiponectin-CTSK axis activation in mice under chronic stress conditions.

Circadian and seasonal variation in onset of acute myocardial infarction.

The aim was to investigate the circadian and seasonal variation of acute myocardial infarction (AMI). Clinical data of 3867 AMI patients hospitalized from November 2010 to October 2019 in the Border Yanbian Minority Autonomous Prefecture, China were collected, and 3158 patients with definite AMI onset times were analyzed. The clinical data analyzed included the time of onset, nationality, age, laboratory data. We divided the patients into 4 groups based on the timepoint of their AMI onsets: 00:00-05:59, 06:00-11:59, 12:00-17:59, and 18:00-23:59. We also divided the patients based on nationality: Chinese Korean and Han groups. We observed that there is a circadian rhythm in the incidence of AMI, and the peak of AMI is in the morning (7:00-9:00). Unexpectedly, the incidence of AMI was significantly lower in the cold winter than that of other 3 warm seasons (P < 0.01) and the peak of AMI presented at the months of the large contrast between day and night temperature difference (over 20°C) like May of Spring and October of Fall. Finally, there was no difference in circadian rhythm between Chinese Korean and Han, although these groups differed in age, body mass index, and the inflammatory cell level. These findings have shown a different seasonal and circadian variation in onset of AMI. Further studies are required to determine the pathophysiological mechanism(s) underlying these differences and to guide prevention of AMI for reducing its mortality and disability.

Prognostic Implications of the Admission Cardiac Troponin I Levels and Door-to-Balloon Time on Clinical Outcomes in Patients with ST-Segment Elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention.

BACKGROUND: The prognostic implications of the admission cTnI level and D2B time combined on in-hospital and 1-year heart failure (HF) and mortality in STEMI patients undergoing a primary percutaneous coronary intervention (PCI) are remain uncertain. METHODS AND RESULTS: We divided the consecutive 1485 STEMI patients who underwent PCI from January 2015 to October 2019 at our hospital into three groups based on their admission cTnI levels: normal group (<0.1 ng/mL), middle group (0.1 to less than 3 ng/mL), and high group (≥3 ng/mL) and into two groups by their D2B times: >90 min (>90-D2B) and ≤90 min (≤90-D2B). During the in-hospital and 1-year follow-up periods, the incidence of composite clinical events increased significantly with the increase in the admission cTnI level (p < 0.05). In-hospital, the composite rate of death and HF events was significantly higher in the >90-D2B group compared to the ≤90-D2B group (p = 0.006), but its influence disappeared in the 1-year follow-up (p > 0.05). A multivariable logistic analysis revealed that, in the ≤90-D2B group, with the exception of the cTnI ≥3 ng/mL patients, the cTnI level had no effect on in-hospital or 1-year outcomes; in >90-D2B group, cTnI ≥3ng/mL increased outcomes in both periods. CONCLUSION: High cTnI levels (≥3 ng/mL) on admission are independent of the D2B time for predicting in-hospital and 1-year cardiac events in STEMI patients undergoing PCI.

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

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 (p67phox, p47phox, p22phox and gp91phox), inflammation (monocyte chemoattractant protein-1, vascular cell adhesion molecule-1, and intracellular adhesion molecule-1), apoptosis (caspase-3, -8, -9), senescence (p16INK4A, 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.