title: CD-NP: a novel engineered dual guanylyl cyclase activator with anti-fibrotic actions in the heart.
abstract: 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.
authors.affiliation: Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Fernando L
authors.initials: FL
authors.lastname: Martin
authors.forename: S Jeson
authors.initials: SJ
authors.lastname: Sangaralingham
authors.forename: Brenda K
authors.initials: BK
authors.lastname: Huntley
authors.forename: Paul M
authors.initials: PM
authors.lastname: McKie
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ichiki
authors.forename: Horng H
authors.initials: HH
authors.lastname: Chen
authors.forename: Josef
authors.initials: J
authors.lastname: Korinek
authors.forename: Gerald E
authors.initials: GE
authors.lastname: Harders
authors.forename: John C
authors.initials: JC
authors.lastname: Burnett
mesh_terms: D000450:Aldosterone / Q000097:blood; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006152:Cyclic GMP / Q000378:metabolism; D004546:Elapid Venoms / Q000737:chemistry / Q000494:pharmacology*; D005355:Fibrosis; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D020098:Natriuretic Peptide, C-Type / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D050705:Receptors, Guanylate Cyclase-Coupled / Q000819:agonists*
chemical_list: C542600:CD-NP natriuretic peptide; D004546:Elapid Venoms; D020098:Natriuretic Peptide, C-Type; D000450:Aldosterone; D050705:Receptors, Guanylate Cyclase-Coupled; D006152:Cyclic GMP