Differential Proteomics Identifies Reticulocalbin-3 as a Novel Negative Mediator of Collagen Production in Human Cardiac Fibroblasts

  • Sci Rep. 2017 Sep 22;7(1):12192. doi: 10.1038/s41598-017-12305-7.
Ernesto Martínez-Martínez  1  2 ,  Jaime Ibarrola  1 ,  Amaya Fernández-Celis  1 ,  Enrique Santamaria  3 ,  Joaquín Fernández-Irigoyen  3 ,  Patrick Rossignol  4 ,  Frederic Jaisser  2  4 ,  Natalia López-Andrés  5  6
Affiliations
  • 1. Cardiovascular Translational Research. Navarrabiomed (Fundación Miguel Servet), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
  • 2. INSERM UMRS 1138 Team 1, Centre de Recherche des Cordeliers, University Pierre and Marie Curie, Paris, France.
  • 3. Proteored-ISCIII, Proteomics Unit, Navarrabiomed, Departamento de Salud, Universidad Pública de Navarra, IDISNA, Navarra Institute for Health Research, Pamplona, Spain.
  • 4. INSERM, Centre d'Investigations Cliniques- Plurithématique 1433, UMR 1116 Université de Lorraine, CHRU de Nancy, FCRIN INI-CRCT, France.
  • 5. Cardiovascular Translational Research. Navarrabiomed (Fundación Miguel Servet), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain. [email protected].
  • 6. INSERM, Centre d'Investigations Cliniques- Plurithématique 1433, UMR 1116 Université de Lorraine, CHRU de Nancy, FCRIN INI-CRCT, France. [email protected].
PMID: 28939891 DOI: 10.1038/s41598-017-12305-7
Abstract

Cardiac fibrosis is characterized by an excessive accumulation of extracellular matrix components, including collagens. Galectin-3 (Gal-3) and Cardiotrophin-1 (CT-1) are two profibrotic molecules that mediate Aldosterone (Aldo)-induced cardiac fibrosis. However the underlying mechanisms are not well defined. Our aim is to characterize changes in the proteome of human cardiac fibroblasts treated with Aldo, Gal-3 or CT-1 to identify new common proteins that might be new therapeutic targets in cardiac fibrosis. Using a quantitative proteomic approach in human cardiac fibroblasts, our results show that Aldo, Gal-3 and CT-1 modified the expression of 30, 17 and 89 proteins respectively, being common the reticulocalbin (RCN) family members. RCN-3 down-regulation triggered by Aldo, Gal-3 and CT-1 was verified. Treatment with recombinant RCN-3 decreased collagens expression in human cardiac fibroblasts through Akt phosphorylation. Interestingly, CRISPR/Cas9-mediated activation of RCN-3 decreased Collagen production in human cardiac fibroblasts. In addition, recombinant RCN-3 blocked the profibrotic effects of Aldo, Gal-3 and CT-1. Interestingly, RCN-3 blunted the increase in collagens expression induced by Other profibrotic stimuli, angiotensin II, in human cardiac fibroblasts. Our results suggest that RCN-3 emerges as a new potential negative regulator of Collagen production and could represent a therapeutic target in the context of cardiac fibrosis.