TY - JOUR
T1 - C53
T2 - A novel particulate guanylyl cyclase B receptor activator that has sustained activity in vivo with anti-fibrotic actions in human cardiac and renal fibroblasts
AU - Chen, Yang
AU - Zheng, Ye
AU - Iyer, Seethalakshmi R.
AU - Harders, Gerald E.
AU - Pan, Shuchong
AU - Chen, Horng H.
AU - Ichiki, Tomoko
AU - Burnett, John C.
AU - Sangaralingham, S. Jeson
N1 - Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/5
Y1 - 2019/5
N2 - 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.
AB - 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.
KW - C-type natriuretic peptide
KW - C53
KW - Fibrosis
KW - NEP
KW - Particulate guanylyl cyclase B receptor
KW - cGMP
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UR - http://www.scopus.com/inward/citedby.url?scp=85064150231&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2019.03.024
DO - 10.1016/j.yjmcc.2019.03.024
M3 - Article
C2 - 30954448
AN - SCOPUS:85064150231
SN - 0022-2828
VL - 130
SP - 140
EP - 150
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
ER -