Inhibition of circulating dipeptidyl-peptidase 3 restores cardiac function in a sepsis-induced model in rats: A proof of concept study

Abstract

Sepsis is a global economic and health burden. Dipeptidyl peptidase 3 (DPP3) is elevated in the plasma of septic patients. The highest levels of circulating DPP3 (cDPP3) are found in non-survivor septic shock patients. The aim of this study was to evaluate the benefits of inhibiting cDPP3 by a specific antibody, Procizumab (PCZ), on cardiac function in an experimental model of sepsis, the caecal ligature and puncture (CLP) model. Rats were monitored by invasive blood pressure and echocardiography. Results are presented as mean ± SD, with p <0.05 considered significant. PCZ rapidly restored left ventricular shortening fraction (from 39 ± 4% to 51 ± 2% before and 30 min after PCZ administration (p = 0.004)). Cardiac output and stroke volume were higher in the CLP + PCZ group when compared to the CLP + PBS group (152 ± 33 mL/min vs 97 ± 25 mL/min (p = 0.0079), and 0.5 ± 0.1 mL vs 0.3 ± 1.0 mL (p = 0.009), respectively) with a markedly reduced plasma DPP3 activity (138 ± 70 U/L in CLP + PCZ group versus 735 ± 255 U/L (p = 0.048) in the CLP + PBS group). Of note, PCZ rapidly reduced oxidative stress in the heart of the CLP + PCZ group when compared to those of the CLP + PBS group (13.3 ± 8.2 vs 6.2 ± 2.5 UI, p = 0.005, 120 min after administration, respectively). Our study demonstrates that inhibition of cDPP3 by PCZ restored altered cardiac function during sepsis in rats.

Monitoring circulating dipeptidyl peptidase 3 (DPP3) predicts improvement of organ failure and survival in sepsis: a prospective observational multinational study

“…5 Department of Intensive Care Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6500 HB Nijmegen, The Netherlands. 6 Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands. 7 Department of Critical Care Medicine, St Luc University Hospital,…”

“…Prognostic properties of cDPP3 have already been demonstrated in critically ill patients suffering from cardiogenic shock and burn [ 3 – 5 ]. Apart from its function as a predictive biomarker of clinical outcome, we further showed, in pre-clinical studies, that cDPP3 exerts negative inotropic effects, working as a cardiac depressant factor [ 6 ]. These deleterious effects were reversed by Procizumab, a monoclonal anti-DPP3 neutralizing antibody [ 3 ].…”

Promotion of vascular integrity in sepsis through modulation of bioactive adrenomedullin and dipeptidyl peptidase 3

“…-Rapidly provokes left ventricular dysfunction in healthy mice [46] -Reduces blood pressure and attenuates adverse cardiac remodelling in a murine hypertension model [21] DPP3-neutralizing antibodies: -Improve survival, and reduce myocardial dysfunction and cardiac oxidative stress markers in a murine sepsis model [49] Underlying specific receptor activity-modifying proteins (RAMP)2 and RAMP3, respectively [58].…”

Alteration of the Renin–Angiotensin–Aldosterone System in Shock: Role of the Dipeptidyl Peptidase 3

“…In addition, DPP3 activity is higher in septic shock than in severe sepsis and higher in decedents than in survivors of septic shock ( 3 ). In a rat model of septic shock with septic cardiomyopathy induced by cecal ligation and puncture, circulating DPP3 activity is also increased ( 7 ). Furthermore, in this preclinical model, inhibition of DPP3 activity with procizumab (α-DPP3 monoclonal antibody) quickly restored cardiac function as measured by left ventricular shortening fraction and improved survival ( 7 ).…”

“…In a rat model of septic shock with septic cardiomyopathy induced by cecal ligation and puncture, circulating DPP3 activity is also increased ( 7 ). Furthermore, in this preclinical model, inhibition of DPP3 activity with procizumab (α-DPP3 monoclonal antibody) quickly restored cardiac function as measured by left ventricular shortening fraction and improved survival ( 7 ). However, the exact mechanism behind the beneficial hemodynamic effect of DPP3 inhibition remains to be identified.…”