Neutrophil Gelatinase-Associated Lipocalin, a Novel Mineralocorticoid Biotarget, Mediates Vascular Profibrotic Effects of Mineralocorticoids.
Fiche publication
Date publication
juillet 2015
Journal
Hypertension (Dallas, Tex. : 1979)
Auteurs
Membres identifiés du Cancéropôle Est :
Pr ROSSIGNOL Patrick
Tous les auteurs :
Tarjus A, Martínez-Martínez E, Amador C, Latouche C, El Moghrabi S, Berger T, Mak TW, Fay R, Farman N, Rossignol P, Zannad F, López-Andrés N, Jaisser F
Lien Pubmed
Résumé
Activation of the mineralocorticoid receptor has been shown to be deleterious in cardiovascular diseases (CVDs). We have recently shown that lipocalin 2 (Lcn2), or neutrophil gelatinase-associated lipocalin (NGAL), is a primary target of aldosterone/mineralocorticoid receptor in the cardiovascular system. Lcn2 is a circulating protein, which binds matrix metalloproteinase 9 and modulates its stability. We hypothesized that Lcn2 could be a mediator of aldosterone/mineralocorticoid receptor profibrotic effects in the cardiovascular system. Correlations between aldosterone and profibrotic markers, such as procollagen type I N-terminal peptide, were investigated in healthy subjects and subjects with abdominal obesity. The implication of Lcn2 in the mineralocorticoid pathway was studied using Lcn2 knockout mice subjected to a nephrectomy/aldosterone/salt (NAS) challenge for 4 weeks. In human subjects, NGAL/matrix metalloproteinase 9 was positively correlated with plasma aldosterone and fibrosis biomarkers. In mice, loss of Lcn2 prevented the NAS-induced increase of plasma procollagen type I N-terminal peptide, as well as the increase of collagen fibers deposition and collagen I expression in the coronary vessels and the aorta. The lack of Lcn2 also blunted the NAS-induced increase in systolic blood pressure. Ex vivo, treatment of human fibroblasts with recombinant Lcn2 induced the expression of collagen I and the profibrotic galectin-3 and cardiotrophin-1 molecules. Our results showed that Lcn2 plays a key role in aldosterone/mineralocorticoid receptor-mediated vascular fibrosis. The clinical data indicate that this may translate in human patients. Lcn2 is, therefore, a new biotarget in cardiovascular fibrosis induced by mineralocorticoid activation.
Mots clés
Acute-Phase Proteins, deficiency, Aldosterone, blood, Animals, Aorta, drug effects, Cardiomyopathy, Hypertrophic, chemically induced, Cells, Cultured, Cytokines, biosynthesis, Female, Fibroblasts, Fibrosis, Galectin 3, biosynthesis, Humans, Hypertension, physiopathology, Hypertrophy, Kidney, pathology, Lipocalin-2, Lipocalins, blood, Male, Mice, Myocardium, cytology, Myocytes, Smooth Muscle, drug effects, Nephrectomy, adverse effects, Obesity, Abdominal, blood, Oncogene Proteins, deficiency, Peptide Fragments, blood, Procollagen, blood, Proto-Oncogene Proteins, blood, Rats, Recombinant Proteins, pharmacology
Référence
Hypertension. 2015 Jul;66(1):158-66