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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.

Author information

1
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.).
2
INSERM UMRS 1138 Team 1, Centre de Recherche des Cordeliers, University Pierre and Marie Curie, Paris, France (E.M.M., M.B., F.J.).
3
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.).
4
CIBERCV, Carlos III Institute of Health, Madrid. Spain (S.R., B.L., M.U.M., J.D., A.G.).
5
Department of Cardiology, Donostia University Hospital, Biodonostia, Basque Country University, San Sebastián, Spain (R.Q.).
6
Proteored-ISCIII, Proteomics Unit, Navarrabiomed, Departamento de Salud, UPNA, IdiSNA, Pamplona, Spain (E.S., J.F.-I.).
7
Department of Cardiology and Cardiac Surgery (G.R., J.D.), Clinic Universtity of Navarra, Pamplona. Spain.
8
INSERM, Centre d'Investigations Cliniques-Plurithématique 1433, UMR 1116 Université de Lorraine, CHRU de Nancy, France (F.J., N.L.-A.).
9
Department of Nephrology (J.D.), Clinic Universtity of Navarra, Pamplona. Spain.

Abstract

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.

KEYWORDS:

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

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