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, gp91phox, 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 H2O2. 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.