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.

Conflict of interest statement

AM reports personal fees from Orion, Servier, Otsuka, Philips, Sanofi, Adrenomed, Epygon and Fire 1 and grants and personal fees from 4TEEN4 Pharmaceuticals GmbH, Abbott and Sphingotec. BD and AB were invited to meetings in Hennigsdorf by 4TEEN4 Pharmaceuticals GmbH. AB is CEO and shareholder at 4TEEN4 Pharmaceuticals GmbH. KS and MK are employees of 4TEEN4 Pharmaceuticals GmbH. Other authors declared no potential conflicts of interest with respect to the research authorship and/or publication of this article. 4TEEN4 Pharmaceuticals GmbH holds patent rights on the DPP3 biomarker and humanized antibody Procizumab. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Design and flow chart of the study.

(A) Schematic representation of the preclinical experiment in rats, including treatments and hemodynamic assessment (BP: blood pressure, CLP: cecal ligation and puncture, PBS: phosphate buffered saline, PCZ: Procizumab, TTE: transthoracic echocardiography). (B) Flowchart of rat’s randomization.

Fig 2. PCZ injection decreased DPP3 plasmatic activity and improved hemodynamics and cardiac function during sepsis.

(A) Plasmatic DPP3 activity in sham + PBS, CLP + PBS and CLP + PCZ groups. Comparisons were made using Wilcoxon rank-sum test. (B) Myocardial qPCR of DPP3 of sham + PBS, CLP + PBS and CLP + PCZ rats. Comparisons were made by Wilcoxon rank-sum test. (C) Schematic representation of the evolution of the left ventricular shortening fraction in time in sham + PBS (blue dashed line), CLP + PBS (grey line) and CLP + PCZ groups (black line) (p

Fig 3. PCZ injection improved myocardial oxidative stress.

Representative images (A) and quantification (B) of DHE staining from myocardial sections of sham + PBS, CLP + PBS and CLP + PCZ rat groups. Myocardial mRNA expression of HO-1 and NQO-1 in sham + PBS, CLP + PBS and CLP + PCZ groups. Comparisons were made by Wilcoxon rank-sum test. (DHE: dihydroethidium, HO-1: heme oxygenase 1, NQO-1: NAD(P)H dehydrogenase (quinone 1)).

Fig 4. cDPP3 is implicated in septic myocardial depression.

Its inhibition by a specific antibody, Procizumab, could be a tool to restore impaired cardiac function. Fig was built using https://smart.servier.com.