C53: A novel particulate guanylyl cyclase B receptor activator that has sustained activity in vivo with anti-fibrotic actions in human cardiac and renal fibroblasts

Yang Chen, Ye Zheng, Seethalakshmi R. Iyer, Gerald E. Harders, Shuchong Pan, Horng Haur Chen, Tomoko Ichiki, John C Jr. Burnett, S Jeson Sangaralingham

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The native particulate guanylyl cyclase B receptor (pGC-B) activator, C-type natriuretic peptide (CNP), induces anti-remodeling actions in the heart and kidney through the generation of the second messenger 3′, 5′ cyclic guanosine monophosphate (cGMP). Indeed fibrotic remodeling, particularly in cardiorenal disease states, contributes to disease progression and thus, has been a key target for drug discovery and development. Although the pGC-B/cGMP system has been perceived as a promising anti-fibrotic pathway, its therapeutic potential is limited due to the rapid degradation and catabolism of CNP by neprilysin (NEP) and natriuretic peptide clearance receptor (NPRC). The goal of this study was to bioengineer and test in vitro and in vivo a novel pGC-B activator, C53. Here we established that C53 selectively generates cGMP via the pGC-B receptor and is highly resistant to NEP and has less interaction with NPRC in vitro. Furthermore in vivo, C53 had enhanced cGMP-generating actions that paralleled elevated plasma CNP-like levels, thus indicating a longer circulating half-life compared to CNP. Importantly in human cardiac fibroblasts (HCFs) and renal fibroblasts (HRFs), C53 exerted robust cGMP-generating actions, inhibited TGFβ-1 stimulated HCFs and HRFs proliferation chronically and suppressed the differentiation of HCFs and HRFs to myofibroblasts. The current findings advance innovation in drug discovery and highlight C53 as a novel pGC-B activator with sustained in vivo activity and anti-fibrotic actions in vitro. Future studies are warranted to explore the efficacy and therapeutic opportunity of C53 targeting fibrosis in cardiorenal disease states and beyond.

Original languageEnglish (US)
Pages (from-to)140-150
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume130
DOIs
StatePublished - May 1 2019
Externally publishedYes

Fingerprint

C-Type Natriuretic Peptide
Cyclic GMP
Fibroblasts
Kidney
Neprilysin
Natriuretic Peptides
Peptide Receptors
Drug Discovery
Guanosine Monophosphate
Myofibroblasts
Second Messenger Systems
Half-Life
Disease Progression
atrial natriuretic factor receptor B
Fibrosis
Therapeutics
In Vitro Techniques

Keywords

  • C-type natriuretic peptide
  • C53
  • cGMP
  • Fibrosis
  • NEP
  • Particulate guanylyl cyclase B receptor

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

C53 : A novel particulate guanylyl cyclase B receptor activator that has sustained activity in vivo with anti-fibrotic actions in human cardiac and renal fibroblasts. / Chen, Yang; Zheng, Ye; Iyer, Seethalakshmi R.; Harders, Gerald E.; Pan, Shuchong; Chen, Horng Haur; Ichiki, Tomoko; Burnett, John C Jr.; Sangaralingham, S Jeson.

In: Journal of Molecular and Cellular Cardiology, Vol. 130, 01.05.2019, p. 140-150.

Research output: Contribution to journalArticle

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abstract = "The native particulate guanylyl cyclase B receptor (pGC-B) activator, C-type natriuretic peptide (CNP), induces anti-remodeling actions in the heart and kidney through the generation of the second messenger 3′, 5′ cyclic guanosine monophosphate (cGMP). Indeed fibrotic remodeling, particularly in cardiorenal disease states, contributes to disease progression and thus, has been a key target for drug discovery and development. Although the pGC-B/cGMP system has been perceived as a promising anti-fibrotic pathway, its therapeutic potential is limited due to the rapid degradation and catabolism of CNP by neprilysin (NEP) and natriuretic peptide clearance receptor (NPRC). The goal of this study was to bioengineer and test in vitro and in vivo a novel pGC-B activator, C53. Here we established that C53 selectively generates cGMP via the pGC-B receptor and is highly resistant to NEP and has less interaction with NPRC in vitro. Furthermore in vivo, C53 had enhanced cGMP-generating actions that paralleled elevated plasma CNP-like levels, thus indicating a longer circulating half-life compared to CNP. Importantly in human cardiac fibroblasts (HCFs) and renal fibroblasts (HRFs), C53 exerted robust cGMP-generating actions, inhibited TGFβ-1 stimulated HCFs and HRFs proliferation chronically and suppressed the differentiation of HCFs and HRFs to myofibroblasts. The current findings advance innovation in drug discovery and highlight C53 as a novel pGC-B activator with sustained in vivo activity and anti-fibrotic actions in vitro. Future studies are warranted to explore the efficacy and therapeutic opportunity of C53 targeting fibrosis in cardiorenal disease states and beyond.",
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AU - Pan, Shuchong

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