Dipeptidyl peptidase‐4 deficiency prevents chronic stress‐induced cardiac remodeling and dysfunction in mice

Abstract Exposure to chronic psychosocial stress is a risk factor for metabolic cardiovascular disorders. Dipeptidyl peptidase‐4 (DPP‐4) plays essential roles in human pathobiology, and we recently showed that DPP‐4 levels are increased by chronic stress in murine models. We here investigated the role of DPP‐4 in stress‐related cardiac injury and dysfunction in mice, focusing on oxidative stress and cardiac apoptosis. Male mice were randomly assigned to non‐stress and two‐week immobilized‐stress groups for biological and morphological studies. On day 14 post‐stress, stress had increased blood pressure, heart weight, cardiac myocyte size, and interstitial fibrosis, impaired cardiac diastolic function, and increased plasma levels of DPP‐4 and glucose. The stressed mice also had increased levels of monocyte chemoattractant protein‐1, inteleukin‐6, gp91 phox , matrix metalloproteinase‐2 (MMP‐2), MMP‐9, tissue inhibitor of MMP‐1/−2, caspase‐8, and Bax genes and/or proteins and lowered levels of Bcl‐2, p‐Akt, and endothelial nitric oxide synthase (eNOS) proteins. DPP‐4 inhibition by either a genetic or pharmacological approach ameliorated the stress‐induced targeted molecular and morphological changes. In vitro, DPP‐4 inhibition also mitigated the alterations in the targeted caspase‐8, Bcl‐2, eNOS, and p‐Akt proteins in H9c2 cardiomyocytes in response to H 2 O 2 . DPP‐4 inhibition appeared to improve the stress‐induced cardiac injury and dysfunction in mice, possibly via the improvement of oxidative stress and apoptosis, suggesting that DPP‐4 could become a novel therapeutic target for chronic psychological stress‐related metabolic cardiovascular disorders.