Molecular signature of mineralocorticoid receptor signaling in cardiomyocytes: from cultured cells to mouse heart.
Excess mineralocorticoid signaling is deleterious for cardiovascular functions, as demonstrated by the beneficial effects of mineralocorticoid receptor (MR) antagonism on morbidity and mortality in patients with heart failure. However, the understanding of signaling pathways after MR activation in the heart remains limited. We performed transcriptomic analyses in the heart of double-transgenic mice with conditional, cardiomyocyte-specific, overexpression of the MR (MRcardio mice) or the glucocorticoid receptor (GR; GRcardio mice). Some of the genes induced in MRcardio mice were selected for comparative evaluation (real time PCR) in vivo in the heart of mice and ex vivo in the MR-expressing cardiomyocyte H9C2 cell line after aldosterone or corticosterone treatment. We demonstrate that chronic MR overexpression in the heart results in a limited number of induced (n = 24) and repressed (n = 22) genes compared with their control littermates. These genes are specifically modulated by MR because there is limited overlap (three induced, four repressed) with the genes that are regulated in the heart of GRcardio mice (compared with control mice: 70 induced, 73 repressed). Interestingly, some MR-induced genes that are up-regulated in vivo in mice are also induced by 24-h aldosterone treatment in H9C2 cells, such as plasminogen activator inhibitor 1 and Serpina-3 (alpha1-antichymotrypsin). The signaling pathways that are affected by long-term activation of MR may be of particular interest to design novel therapeutic targets in cardiac diseases.
Latouche
Celine
C
Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 872 Team 1, Centre de Recherches des Cordeliers, Université Pierre et Marie Curie, 15 Rue de l'Ecole de Médecine, 75006 Paris, France.
Sainte-Marie
Yannis
Y
Steenman
Marja
M
Castro Chaves
Paulo
P
Naray-Fejes-Toth
Aniko
A
Fejes-Toth
Geza
G
Farman
Nicolette
N
Jaisser
Frederic
F
D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D003345:Corticosterone / Q000494:pharmacology; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
D018161:Receptors, Mineralocorticoid; D015843:Serpins; D000450:Aldosterone; D004318:Doxycycline; D003345:Corticosterone