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Hypertension. 2019 Mar;73(3):602-611. doi: 10.1161/HYPERTENSIONAHA.118.11874.

CT-1 (Cardiotrophin-1)-Gal-3 (Galectin-3) Axis in Cardiac Fibrosis and Inflammation.

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From the Cardiovascular Translational Research, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona. Spain (E.M.-M., J.I., A.F.-C., N.L.-A.).
INSERM UMRS 1138 Team 1, Centre de Recherche des Cordeliers, University Pierre and Marie Curie, Paris, France (E.M.M., M.B., F.J.).
Program of Cardiovascular Diseases, CIMA University of Navarra and IdiSNA, Pamplona. Spain (C.B., S.R., B.L., M.U.M., J.D., A.G.).
CIBERCV, Carlos III Institute of Health, Madrid. Spain (S.R., B.L., M.U.M., J.D., A.G.).
Department of Cardiology, Donostia University Hospital, Biodonostia, Basque Country University, San Sebastián, Spain (R.Q.).
Proteored-ISCIII, Proteomics Unit, Navarrabiomed, Departamento de Salud, UPNA, IdiSNA, Pamplona, Spain (E.S., J.F.-I.).
Department of Cardiology and Cardiac Surgery (G.R., J.D.), Clinic Universtity of Navarra, Pamplona. Spain.
INSERM, Centre d'Investigations Cliniques-Plurithématique 1433, UMR 1116 Université de Lorraine, CHRU de Nancy, France (F.J., N.L.-A.).
Department of Nephrology (J.D.), Clinic Universtity of Navarra, Pamplona. Spain.


Myocardial fibrosis is a main contributor to the development of heart failure (HF). CT-1 (cardiotrophin-1) and Gal-3 (galectin-3) are increased in HF and associated with myocardial fibrosis. The aim of this study is to analyze whether CT-1 regulates Gal-3. Proteomic analysis revealed that Gal-3 was upregulated by CT-1 in human cardiac fibroblasts in parallel with other profibrotic and proinflammatory markers. CT-1 upregulation of Gal-3 was mediated by ERK (extracellular signal-regulated kinase) 1/2 and Stat-3 (signal transducer and activator of transcription 3) pathways. Male Wistar rats and B6CBAF1 mice treated with CT-1 (20 µg/kg per day) presented higher cardiac Gal-3 levels and myocardial fibrosis. In CT-1-treated rats, direct correlations were found between cardiac CT-1 and Gal-3 levels, as well as between Gal-3 and perivascular fibrosis. Gal-3 genetic disruption in human cardiac fibroblasts and pharmacological Gal-3 inhibition in mice prevented the profibrotic and proinflammatory effects of CT-1. Dahl salt-sensitive hypertensive rats with diastolic dysfunction showed increased cardiac CT-1 and Gal-3 expression together with cardiac fibrosis and inflammation. CT-1 and Gal-3 directly correlated with myocardial fibrosis. In HF patients, myocardial and plasma CT-1 and Gal-3 were increased and directly correlated. In addition, HF patients with high CT-1 and Gal-3 plasma levels presented an increased risk of cardiovascular death. Our data suggest that CT-1 upregulates Gal-3 which, in turn, mediates the proinflammatory and profibrotic myocardial effects of CT-1. The elevation of both molecules in HF patients identifies a subgroup of patients with a higher risk of cardiovascular mortality. The CT-1/Gal-3 axis emerges as a candidate therapeutic target and a potential prognostic biomarker in HF.


cardiotrophin-1; fibroblasts; galectin-3; heart failure; inflammation

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