Research Article Open Access
Volume 1 | Issue 1 | DOI: https://doi.org/10.33696/Proteomics.1.003

Identification of the Molecular Basis of Anti-fibrotic Effects of Soluble Guanylate Cyclase Activator Using the Human Lung Fibroblast

  • 1Cardiometabolic Disease Biology-Discovery, Merck & Co., Inc., South San Francisco, CA, USA
  • 2Scientific informatics, Merck & Co., Inc., South San Francisco, CA, USA
  • 3Discovery pGx, Merck & Co., Inc., West Point, PA, USA
  • 4Chemistry Capabilities Accelerate Therapeutics, Merck & Co., Inc., Kenilworth, NJ, USA
  • 5Cardiovascular, Metabolic, Renal, Ophthalmology Biology-Discovery, Merck & Co., Inc., South San Francisco, CA, USA
  • #Present Address: Maze Therapeutics, South San Francisco, CA USA
+ Affiliations - Affiliations

Corresponding Author

Sunhwa Kim, sunhwa.kim@merck.com

Received Date: September 09, 2020

Accepted Date: November 11, 2020


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 ß (TGFß), 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.


Phosphoproteome; Soluble guanylate cyclase activator; Transforming growth factor 1; Fibrosis

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