Aldosterone inhibits antifibrotic factors in mouse hypertensive heart
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Aldosterone inhibits antifibrotic factors in mouse hypertensive heart. / Azibani, Feriel; Benard, Ludovic; Schlossarek, Saskia; Merval, Regine; Tournoux, François; Fazal, Loubina; Polidano, Evelyne; Launay, Jean-Marie; Carrier, Lucie; Chatziantoniou, Christos; Samuel, Jane-Lise; Delcayre, Claude.
In: HYPERTENSION, Vol. 59, No. 6, 6, 2012, p. 1179-1187.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Aldosterone inhibits antifibrotic factors in mouse hypertensive heart
AU - Azibani, Feriel
AU - Benard, Ludovic
AU - Schlossarek, Saskia
AU - Merval, Regine
AU - Tournoux, François
AU - Fazal, Loubina
AU - Polidano, Evelyne
AU - Launay, Jean-Marie
AU - Carrier, Lucie
AU - Chatziantoniou, Christos
AU - Samuel, Jane-Lise
AU - Delcayre, Claude
PY - 2012
Y1 - 2012
N2 - 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-?1 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).
AB - 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-?1 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).
KW - Animals
KW - Male
KW - Female
KW - Cells, Cultured
KW - Mice
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Mice, Transgenic
KW - Blotting, Western
KW - Animals, Newborn
KW - Organ Size
KW - Antigens, CD/genetics/metabolism
KW - Blood Pressure
KW - Fibrosis
KW - Gene Expression/drug effects
KW - Myocardium/metabolism/pathology
KW - Aldosterone/metabolism/pharmacology
KW - Aldosterone Synthase/genetics/metabolism
KW - Antigens, Differentiation, Myelomonocytic/genetics/metabolism
KW - Bone Morphogenetic Protein 4/genetics/metabolism
KW - Galectin 3/genetics/metabolism
KW - Hyperaldosteronism/genetics/metabolism/physiopathology
KW - Hypertension/genetics/metabolism/physiopathology
KW - Mineralocorticoid Receptor Antagonists/pharmacology
KW - Natriuretic Peptide, Brain/genetics/metabolism
KW - Renin/genetics/metabolism
KW - Spironolactone/analogs & derivatives/pharmacology
KW - Animals
KW - Male
KW - Female
KW - Cells, Cultured
KW - Mice
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Mice, Transgenic
KW - Blotting, Western
KW - Animals, Newborn
KW - Organ Size
KW - Antigens, CD/genetics/metabolism
KW - Blood Pressure
KW - Fibrosis
KW - Gene Expression/drug effects
KW - Myocardium/metabolism/pathology
KW - Aldosterone/metabolism/pharmacology
KW - Aldosterone Synthase/genetics/metabolism
KW - Antigens, Differentiation, Myelomonocytic/genetics/metabolism
KW - Bone Morphogenetic Protein 4/genetics/metabolism
KW - Galectin 3/genetics/metabolism
KW - Hyperaldosteronism/genetics/metabolism/physiopathology
KW - Hypertension/genetics/metabolism/physiopathology
KW - Mineralocorticoid Receptor Antagonists/pharmacology
KW - Natriuretic Peptide, Brain/genetics/metabolism
KW - Renin/genetics/metabolism
KW - Spironolactone/analogs & derivatives/pharmacology
U2 - 10.1161/HYPERTENSIONAHA.111.190512
DO - 10.1161/HYPERTENSIONAHA.111.190512
M3 - SCORING: Journal article
C2 - 22547442
VL - 59
SP - 1179
EP - 1187
JO - HYPERTENSION
JF - HYPERTENSION
SN - 0194-911X
IS - 6
M1 - 6
ER -
