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

被引:26
作者
Chen, Yang [1 ,3 ]
Zheng, Ye [1 ]
Iyer, Seethalakshmi R. [1 ]
Harders, Gerald E. [1 ]
Pan, Shuchong [1 ]
Chen, Horng H. [1 ]
Ichiki, Tomoko [1 ]
Burnett, John C., Jr. [1 ,2 ]
Sangaralingham, S. Jeson [1 ,2 ]
机构
[1] Dept Cardiovasc Med, Cardiorenal Res Lab, 200 First St SW, Rochester, MN 55905 USA
[2] Dept Physiol & Biomed Engn, Rochester, MN USA
[3] Mayo Clin, Grad Sch Biomed Sci, Rochester, MN USA
关键词
C53; C-type natriuretic peptide; Particulate guanylyl cyclase B receptor; Fibrosis; cGMP; NEP; ATRIAL-NATRIURETIC-PEPTIDE; C-TYPE; TGF-BETA; HEART-FAILURE; HUMAN KIDNEY; FIBROSIS; THERAPEUTICS; SECRETION; BIOMARKER; PATHWAY;
D O I
10.1016/j.yjmcc.2019.03.024
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 TGF beta-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.
引用
收藏
页码:140 / 150
页数:11
相关论文
共 53 条
[1]  
BENNETT BD, 1991, J BIOL CHEM, V266, P23060
[2]   Novel Protein Therapeutics for Systolic Heart Failure [J].
Chen, Horng H. ;
Glockner, James F. ;
Schirger, John A. ;
Cataliotti, Alessandro ;
Redfield, Margaret M. ;
Burnett, John C., Jr. .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2012, 60 (22) :2305-2312
[3]   CRRL269: a novel designer and renal-enhancing pGC-A peptide activator [J].
Chen, Yang ;
Harty, Gail J. ;
Huntley, Brenda K. ;
Iyer, Seethalakshmi R. ;
Heublein, Denise M. ;
Harders, Gerald E. ;
Meems, Laura ;
Pan, Shuchong ;
Sangaralingham, S. Jeson ;
Ichiki, Tomoko ;
Burnett, John C., Jr. .
AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 2018, 314 (03) :R407-R414
[4]   Biochemistry, Therapeutics, and Biomarker Implications of Neprilysin in Cardiorenal Disease [J].
Chen, Yang ;
Burnett, John C., Jr. .
CLINICAL CHEMISTRY, 2017, 63 (01) :108-115
[5]   SYNTHESIS AND LOCALIZATION OF C-TYPE NATRIURETIC PEPTIDE IN MAMMALIAN KIDNEY [J].
DEAN, AD ;
VEHASKARI, VM ;
GREENWALD, JE .
AMERICAN JOURNAL OF PHYSIOLOGY, 1994, 266 (03) :F491-F496
[6]   Dendroaspis natriuretic peptide and the designer natriuretic peptide, CD-NP, are resistant to proteolytic inactivation [J].
Dickey, Deborah M. ;
Potter, Lincoln R. .
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 2011, 51 (01) :67-71
[7]   A Familial Mutation Renders Atrial Natriuretic Peptide Resistant to Proteolytic Degradation [J].
Dickey, Deborah M. ;
Yoder, Andrea R. ;
Potter, Lincoln R. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (29) :19196-19202
[8]   Transforming growth factor (TGF)-β signaling in cardiac remodeling [J].
Dobaczewski, Marcin ;
Chen, Wei ;
Frangogiannis, Nikolaos G. .
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 2011, 51 (04) :600-606
[9]   Natriuretic peptide receptor-B in adult rat ventricle is predominantly confined to the nonmyocyte population [J].
Doyle, DD ;
Upshaw-Earley, J ;
Bell, EL ;
Palfrey, HC .
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2002, 282 (06) :H2117-H2123
[10]   Peptide therapeutics: current status and future directions [J].
Fosgerau, Keld ;
Hoffmann, Torsten .
DRUG DISCOVERY TODAY, 2015, 20 (01) :122-128