Influence of adrenomedullin on the enzymatic activity of dipeptidyl peptidase 3 in vitro

Circulating Dipeptidyl Peptidase 3 (DPP3) hydrolyses dipeptides from the amino terminus of its substrates and excess levels represent a target for the treatment of cardiogenic shock. Known substrates include Angiotensin II (Ang II), but there might be more. Adrenomedullin (ADM) is a 52-mer peptide regulating vascular tone and integrity, which also is a therapeutic target for the treatment of shock. The pathways leading to shock involving DPP3 and ADM have been considered independent so far. Here, we assessed the influence of ADM on the activity of DPP3 in vitro using an established assay. ADM inhibited DPP3 activity at a similar IC50 concentration (6.5 µM) as the cognate substrate Ang II (6.6 µM). As opposed to Ang II, ADM was barely cleaved by DPP3 in vitro. Stepwise C-terminal truncation of ADM essentially did not change its inhibitory effect. Inhibition of DPP3 activity by ADM was reversed by an anti-N-terminal ADM antibody.