2. Academic Validation
  3. Differential modulation of the sGC-cGMP pathway by sGC stimulators and activators in human lung cells

Differential modulation of the sGC-cGMP pathway by sGC stimulators and activators in human lung cells

  • Biochem Pharmacol. 2026 Jun:248:117866. doi: 10.1016/j.bcp.2026.117866.
Paula Montero 1,  María Amparo Bayarri 2,  Inés Roger 3,  Juan Escrivá 4,  Carolina Ferrer-Gomez 5,  Javier Milara 6,  Julio Cortijo 2
Affiliations

Affiliations

  • 1 Department of Pharmacology, Faculty of Medicine, University of Valencia 46010 Valencia, Spain; Research Foundation of the General University Hospital of Valencia (FIHGUV), 46014 Valencia, Spain; Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), Health Institute Carlos III, 28029 Madrid, Spain. Electronic address: [email protected].
  • 2 Department of Pharmacology, Faculty of Medicine, University of Valencia 46010 Valencia, Spain.
  • 3 Department of Pharmacology, Faculty of Medicine, University of Valencia 46010 Valencia, Spain; Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), Health Institute Carlos III, 28029 Madrid, Spain; Faculty of Health Sciences, Universidad Europea de Valencia 46185 Valencia, Spain.
  • 4 Thoracic Surgery Unit, University and Polytechnic Hospital La Fe, Valencia, Spain.
  • 5 Anesthesiology and Intensive Care Unit, General University Hospital of Valencia (CHGUV), 46014 Valencia, Spain.
  • 6 Department of Pharmacology, Faculty of Medicine, University of Valencia 46010 Valencia, Spain; Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), Health Institute Carlos III, 28029 Madrid, Spain; Pharmacy Unit, General University Hospital of Valencia (CHGUV), 46014 Valencia, Spain.
PMID: 41794266 DOI: 10.1016/j.bcp.2026.117866
Abstract

Chronic lung diseases are characterized by oxidative stress, inflammation, and fibroproliferation, conditions that impair nitric oxide (NO)-soluble Guanylate Cyclase (sGC)-cyclic GMP (cGMP) signaling. Here, we investigated the differential effects of an sGC stimulator (riociguat) and an sGC activator (cinaciguat), alone or combined with the PDE5 Inhibitor sildenafil, in primary human pulmonary cells exposed to cigarette smoke extract (CSE). Lung tissue from COPD and asthma patients displayed reduced sGC α1 and β1 expression, and CSE induced concentration-dependent oxidation of the sGC heme group, diminishing responsiveness to NO and to riociguat. Cinaciguat, but not riociguat, maintained cGMP production under oxidizing conditions, while co-treatment with sildenafil further increased cGMP levels for both drugs. In epithelial cells, fibroblasts, neutrophils, and endothelial monolayers, cinaciguat and riociguat attenuated CSE-induced oxidative stress, inflammatory cell adhesion, and profibrotic gene expression, with cinaciguat-particularly in combination with sildenafil-showing more robust effects across endpoints. These findings identify distinct pharmacodynamic profiles for sGC stimulators versus activators under oxidative conditions and support sGC modulation as a potential therapeutic approach in oxidative chronic lung diseases.

Keywords

Cigarette smoke; Oxidative stress; Pulmonary cells; sGC modulators.

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