title: Aldosterone inhibits antifibrotic factors in mouse hypertensive heart.
abstract: The renin-angiotensin-aldosterone system is involved in the arterial hypertension-associated cardiovascular remodeling. In this context, the development of cardiac fibrosis results from an imbalance between profibrotic and antifibrotic pathways, in which the role of aldosterone is yet not established. To determine the role of intracardiac aldosterone in the development of myocardial fibrosis during hypertension, we used a double transgenic model (AS-Ren) of cardiac hyperaldosteronism (AS) and systemic hypertension (Ren). The 9-month-old hypertensive mice had cardiac fibrosis, and hyperaldosteronism enhanced the fibrotic level. The mRNA levels of connective tissue growth factor and transforming growth factor-β1 were similarly increased in Ren and AS-Ren mice compared with wild-type and AS mice, respectively. Hyperaldosteronism combined with hypertension favored the macrophage infiltration (CD68(+) cells) in heart, and enhanced the mRNA level of monocyte chemoattractant protein 1, osteopontin, and galectin 3. Interestingly, in AS-Ren mice the hypertension-induced increase in bone morphogenetic protein 4 mRNA and protein levels was significantly inhibited, and B-type natriuretic peptide expression was blunted. The mineralocorticoid receptor antagonist eplerenone restored B-type natriuretic peptide and bone morphogenetic protein 4 levels and decreased CD68 and galectin 3 levels in AS-Ren mice. Finally, when hypertension was induced by angiotensin II infusion in wild-type and AS mice, the mRNA profiles did not differ from those observed in Ren and AS-Ren mice, respectively. The aldosterone-induced inhibition of B-type natriuretic peptide and bone morphogenetic protein 4 expression was confirmed in vitro in neonatal mouse cardiomyocytes. Altogether, we demonstrate that, at the cardiac level, hyperaldosteronism worsens hypertension-induced fibrosis through 2 mineralocorticoid receptor-dependent mechanisms, activation of inflammation/galectin 3-induced fibrosis and inhibition of antifibrotic factors (B-type natriuretic peptide and bone morphogenetic protein 4).
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U942 and Université Paris-Diderot, Paris, France.
authors.forename: Feriel
authors.initials: F
authors.lastname: Azibani
authors.forename: Ludovic
authors.initials: L
authors.lastname: Benard
authors.forename: Saskia
authors.initials: S
authors.lastname: Schlossarek
authors.forename: Regine
authors.initials: R
authors.lastname: Merval
authors.forename: François
authors.initials: F
authors.lastname: Tournoux
authors.forename: Loubina
authors.initials: L
authors.lastname: Fazal
authors.forename: Evelyne
authors.initials: E
authors.lastname: Polidano
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Launay
authors.forename: Lucie
authors.initials: L
authors.lastname: Carrier
authors.forename: Christos
authors.initials: C
authors.lastname: Chatziantoniou
authors.forename: Jane-Lise
authors.initials: JL
authors.lastname: Samuel
authors.forename: Claude
authors.initials: C
authors.lastname: Delcayre
mesh_terms: D000450:Aldosterone / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000378:metabolism; D001794:Blood Pressure; D015153:Blotting, Western; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics / Q000378:metabolism; D000077545:Eplerenone; D005260:Female; D005355:Fibrosis; D037502:Galectin 3 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006929:Hyperaldosteronism / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism*; D009929:Organ Size; D012083:Renin / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D000097382:CD68 Molecule
chemical_list: D000450:Aldosterone; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D055415:Bone Morphogenetic Protein 4; D019405:Cytochrome P-450 CYP11B2; D000077545:Eplerenone; D037502:Galectin 3; D000451:Mineralocorticoid Receptor Antagonists; D020097:Natriuretic Peptide, Brain; D012083:Renin; D013148:Spironolactone; C081026:CD68 protein, mouse; D000097382:CD68 Molecule