Neprilysin and natriuretic peptide receptor C – new, interesting targets for heart failure therapy No conflicts of interest decleared K. Kodziszewska1, P. Leszek1, B. Sochanowicz, K. Brzoska2, M. Pronicki3, T. Zieliński2 1Department of Heart Failure and Transplantology, Institute of Cardiology, Warsaw, Poland 2Institute of Nuclear Chemistry and Technology, Centre for Radiobiology and Biological Dosimetry, Warsaw, Poland 3Department of Pathology, Children’s Memorial Health Institute, Warsaw, Poland

Natriuretic peptide clearance system Type natriuretic peptide receptor C Binds all natriuretic peptides (NP) with similar affinity Eliminates NPs from the system by internalization/lyzosomal degradation Upon stimulation with ANP and/or CNP produces biological effect via adenylyl cyclase and PLC pathways Neutral endopeptidase Membrane-bound and soluble forms Distributed in a variety of tissues Breaks down a variety of substances, bradykinin, angiotensin -1,-2,-3, endothelin -1,-2, and -3 Breaks down NPs in the order of affinity CNP=ANP>BNP

Study material Study group – cardiac tissue obtained from 43 patients subject to heart transplantation due to advanced heart failure Control group – hearts obtained from 12 healthy organ donors not allocated to transplantation due to technical reasons

Type C natriuretic peptide receptor mRNA (PCR) Protein - ELISA p=0.0000131 p=0.0014 Relative expression of NPR-C receptor in a non-failing vs. failing heart

Cardiac expression and function of neutral endopeptidase Protein - ELISA Function - FLUORIMETRY p<0.00002 p=0.4181 Neutral endopeptidase expression and activity in non-failing vs. failing hearts

Conclusions Heart failure is associated with augmented NPR-C expression on mRNA level However, on a protein level NPR-C expression is reduced Neutral endopeptidase levels remain unchanged in failing vs. non-failing hearts, while its activity significantly increases in heart failure – a finding that strongly supports the rationale behind clinical application of NEP inhibitors