The source of liberation of dipeptidyl peptidase 3 (DPP3), a newly emerged cardiac biomarker, in pathological situations

Abstract

Dipeptidyl peptidase 3 (DPP3) is a zinc dependent aminopeptidase that cleaves dipeptides from the N- terminus of several substrates such as angiotensins. DPP3 is an intracellular protein. It has also been detected in the circulation of healthy and sick individuals being known as circulating DPP3 (cDPP3). cDPP3 has emerged as a biomarker and a therapeutic target in acute cardiac stress. Despite the well-known ubiquitous expression of DPP3 in physiological situations, its expression and source of release in pathological conditions remain to be explored. This study aimed to evaluate DPP3 expression in cardiac stress conditions. C57BL6/J mice were subjected to cardiac dysfunction using two different pharmacological models: 1- Isoproterenol (ISO) model: injection of 150 mg/kg of ISO every 12 h for two days; 2- Doxorubicin (DOX) model: injection of 4 mg/kg/day of DOX for 6 days. Blood samples, organs, and bone marrow (cells and supernatant) were collected at the end of each protocol. DPP3 protein expression was evaluated by western-blot. Enzymatic activity of DPP3 was measured by luminometric immunoassay (DPP3-LIA). Our results showed different patterns of DPP3 expression based on pathological condition. Mice in ISO group showed a significantly higher DPP3 protein expression in bone marrow, both cells and supernatant, compared to control group (1.8X, P < 0.05). In consistence with this, DPP3 enzymatic activity was significantly increased in both bone marrow supernatant and plasma in these mice (1.4X, P < 0.05) and (1.3X, P < 0.05) respectively, indicating that bone marrow might be responsible for releasing DPP3 into the surrounding microenvironment and into the circulation. However, DPP3 expression was decreased in the spleen of ISO mice (0.5X, P < 0.05). This decrease could be explained by spleen-contraction following ISO injection, a phenomenon already described in the literature, allowing greater release of red blood cells, highly expressing DPP3, into bloodstream. On the other hand, in Dox model, only an up-regulation of DPP3 in the spleen (1.7X, P < 0.05) was reported. An increase of DPP3 activity in plasma but not in bone marrow supernatant was remarked. Our results show that DPP3 expression varies based on the type of model used to induce cardiac dysfunction. It seems that main hematopoietic organs (spleen and bone marrow) might represent sources of cDPP3.