Dipeptidyl peptidase 3 (DPP3) is a zinc-dependent metallopeptidase cleaving the N-terminal extremity of various bioactive peptides including angiotensins. Angiotensin II is a vasoactive peptide also known to have an inotropic effect. Although the plasmatic concentration of DPP3 is low in healthy human and animals, an increase in plasmatic DPP3 concentration and activity has been observed during circulatory failure. In such situation DPP3 could play a pathological role, putatively via an excess in angiotensin cleavage.

To investigate 1. Hemodynamics changes induced by DPP3 in healthy mice; 2. Concomitant changes in circulating renin-angiotensin-aldosterone system (RAAS) mediators.

Healthy, 10-week-old C57BL/6J male mice were subjected to intravenous injection of purified human DPP3 (0.55mg/kg), anti-DPP3 antibody (Procizumab, 10mg/kg) or phosphate-buffered saline (PBS). Cardiovascular function was monitored using echocardiography, invasive blood pressure by catheterism of the femoral artery and renal blood flow with an invasive time-of-flight flowmeter. Circulating angiotensin peptides, aldosterone, and renin activity were measured by liquid chromatography-mass spectrometry/mass spectroscopy.

DPP3 injection induced a decrease in left ventricular systolic function as measured by the left ventricular shortening fraction with a maximal depression of −12±8% (P=0.01) and an increase in mean renal blood flow (maximal increase +45±18%, P=0.02) gradually returning to baseline values in 120min and 30min, respectively. Invasive blood pressure remained stable throughout the experiment. Additionaly; DPP3 were associated with a significant decrease in circulating angiotensin II (−66%, P<0.01), angiotensin III (−82%, P<0.001) and angiotensin IV (−68%, P<0.001) and a significant increase in angiotensin I (+108%, P=0.02) compared to PBS injected mice. Conversely, procizumab injection resulted in increased circulating angiotensin II (+113%, P<0.01), angiotensin III (+75%, P=0.02), angiotensin 1-5 (+167%, P=0.02) angiotensin 1-7 (+60%, P=0.01) as well as increased aldosterone (+49%, P=0.04), when compared to PBS injected mice.

DPP3 injection induced cardiac dysfunction and renal blood flow increase in healthy mice. Additionally, DPP3 injection is associated with a decrease in angiotensins levels including angiotensin II, which was reversed with procizumab. Future work on the relation between hemodynamic changes and DPP3-induced modulation of the RAAS is needed.