RT Journal Article
SR Electronic
T1 Identification of the Molecular Basis of Anti-fibrotic Effects of Soluble Guanylate Cyclase Activator Using the Human Lung Fibroblast Phosphoproteome
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.06.12.148908
DO 10.1101/2020.06.12.148908
A1 Kim, Sunhwa
A1 Saigal, Ashmita
A1 Zhao, Weilong
A1 Amini, Peyvand
A1 Tamburino, Alex M.
A1 Raghavan, Subharekha
A1 Hoek, Maarten
YR 2020
UL http://biorxiv.org/content/early/2020/06/14/2020.06.12.148908.abstract
AB Idiopathic pulmonary fibrosis (IPF) is an irreversible and progressive fibrotic lung disease. Advanced IPF patients often demonstrate pulmonary hypertension, which severely impairs patients’ quality of life. The critical physiological roles of soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway have been well characterized in vasodilation and the corresponding therapies and pathway agonists have shown clinical benefits in treating hypertension. In recent years, many preclinical studies have demonstrated anti-fibrotic efficacy of sGC-cGMP activation in various experimental fibrosis models but the molecular basis of the efficacy in these models are not well understood. Also, sGC pathway agonism has demonstrated encouraging clinical benefits in advanced IPF patients (NCT00517933). Here, we have revealed the novel phosphorylation events downstream of sGC activation in human lung fibroblasts using phosphoproteomics. sGCact A, a potent and selective sGC activator, significantly attenuated more than 2,000 phosphorylation sites. About 20% of phosphorylation events, attenuated by transforming growth factor β (TGFβ), a master regulator of fibrosis, were further dysregulated in the sGCact A co-treated lung fibroblasts. The overall magnitude and diversity of the sGCact A phosphoproteome was extensive. Further investigation would be required to understand how these newly identified changes facilitate human pulmonary fibrosis.Competing Interest StatementSunhwa Kim, Ashmita Saigal, Weilong Zhao, Peyvand Amini, Alex M. Tamburino, Subharekha Raghavan, Saswata Talukdar are employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and stockholder at Merck & Co., Inc., Kenilworth, NJ, USA. Maarten Hoek was an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA when the study was conducted and is currently an employee of Maze Therapeutics, South San Francisco, CA, USA. Maarten Hoek is a stockholder at Merck & Co., Inc., Kenilworth, NJ, USA. (IPF)Idiopathic pulmonary fibrosis;(sGC)Soluble guanylaate cyclase;(cGMP)Cyclic guanosine monophosphate;(sGCact)sGC activators;(sGCstim)sGC stimulators;(HFL1)human lung fibroblast 1;(SMA)α-smooth muscle actin;(SRRM2)Serine/arginine repetitive matrix protein 2