CD-NP: a novel engineered dual guanylyl cyclase activator with anti-fibrotic actions in the heart

• Published in: PloS one Vol. 7; no. 12; p. e52422
• Main Authors: Martin, Fernando L, Sangaralingham, S Jeson, Huntley, Brenda K, McKie, Paul M, Ichiki, Tomoko, Chen, Horng H, Korinek, Josef, Harders, Gerald E, Burnett, Jr, John C
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.12.2012; Public Library of Science (PLoS)
• Subjects: Activation; Aging; Aldosterone; Aldosterone - blood; Amino Acid Sequence; Analysis; Animals; Apoptosis; Biology; Cell Line; Chemical compounds; Collagen; Cyclic GMP; Cyclic GMP - metabolism; Dendroaspis; Elapid Venoms - chemistry; Elapid Venoms - pharmacology; Fibroblasts; Fibrosis; Gene expression; Glucocorticoids; Guanylate cyclase; Heart; Heart - drug effects; Heart diseases; Heart Ventricles - metabolism; Heart Ventricles - pathology; Humans; Laboratories; Male; Medical imaging; Medical innovations; Medicine; Molecular Sequence Data; Myocardium - metabolism; Myocardium - pathology; Natriuretic Peptide, C-Type - chemistry; Natriuretic Peptide, C-Type - pharmacology; Natriuretic peptides; Nephrectomy; Peptides; Pharmacology; Plasma; Rats; Receptors; Receptors, Guanylate Cyclase-Coupled - agonists; Rodents; Ventricle; United States > US; Minnesota
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0052422

Natriuretic peptides (NPs) are cardioprotective through the activation of guanylyl cyclase (GC) receptors A and B. CD-NP, also known as cenderitide, is a novel engineered NP that was designed to uniquely serve as a first-in-class dual GC receptor agonist. Recognizing the aldosterone suppressing actions of GC-A activation and the potent inhibitory actions on collagen synthesis and fibroblast proliferation through GC-B activation, the current study was designed to establish the anti-fibrotic actions of CD-NP, administered subcutaneously, in an experimental rat model of early cardiac fibrosis induced by unilateral nephrectomy (UNX). Our results demonstrate that a two week subcutaneous infusion of CD-NP significantly suppresses left ventricular fibrosis and circulating aldosterone, while preserving both systolic and diastolic function, in UNX rats compared to vehicle treated UNX rats. Additionally we also confirmed, in vitro, that CD-NP significantly generates the second messenger, cGMP, through both the GC-A and GC-B receptors. Taken together, this novel dual GC receptor activator may represent an innovative anti-fibrotic therapeutic agent.