Circulating dipeptidyl peptidase 3 is a myocardial depressant factor: dipeptidyl peptidase 3 inhibition rapidly and sustainably improves haemodynamics

Deniau, B.; Rehfeld, L.; Santos, K.; Dienelt, A.; Azibani, F.; Sadoune, M.; Kounde, P.R.; Samuel, J.L.; Tolpannen, H.; Lassus, J.; Harjola, V.-P.; Vodovar, N.; Bergmann, A.; Hartmann, O.; Mebazaa, A.; Blet, A.

European Journal of Heart Failure 22(2): 290-299

2020


ISSN/ISBN: 1879-0844
PMID: 31472040
DOI: 10.1002/ejhf.1601
Accession: 069295296

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Abstract
Acute heart failure is a high mortality disease and its pathophysiology is not completely understood. Dipeptidyl peptidase 3 (DPP3) is a cytosolic enzyme involved in angiotensin II and enkephalins cleavage. The aim of this study was to investigate the association of circulating DPP3 (cDPP3) levels and mortality in cardiogenic shock patients and to determine the effects of high cDPP3 on organ function in a heart failure (HF) model in mice. cDPP3 was measured in 174 patients in cardiogenic shock and high cDPP3 levels were associated with an increased short-term mortality risk (standardized hazard ratio: 1.4 (1.1-1.8)) and severe organ dysfunction. Additionally, a rapid decrease in cDPP3 in cardiogenic shock patients within 24 h of admission was associated with a favourable outcome. This study showed that injection of DPP3 induced myocardial depression (-10 ± 2% of shortening fraction) and impaired kidney haemodynamics (+0.30 ± 0.02 of renal resistive index) in healthy mice. cDPP3 inhibition by Procizumab, a specific antibody directed against cDPP3, promptly normalized cardiac function and kidney haemodynamics in an acute heart failure mouse model, with a marked reduction in oxidative stress and inflammatory signalling. Our study demonstrated cDPP3 is a newly discovered myocardial depressant factor, the levels of which at admission are associated with mortality in severe HF patients. Furthermore, inhibition of cDPP3 by Procizumab improved haemodynamics in a mouse model of HF. Our results suggest that DPP3 could be a new biomarker and biotarget for severe HF.