Reversible cardiac fibrosis and heart failure induced by conditional expression of an antisense mRNA of the mineralocorticoid receptor in cardiomyocytes.
Cardiac failure is a common feature in the evolution of cardiac disease. Among the determinants of cardiac failure, the renin-angiotensin-aldosterone system has a central role, and antagonism of the mineralocorticoid receptor (MR) has been proposed as a therapeutic strategy. In this study, we questioned the role of the MR, not of aldosterone, on heart function, using an inducible and cardiac-specific transgenic mouse model. We have generated a conditional knock-down model by expressing solely in the heart an antisense mRNA directed against the murine MR, a transcription factor with unknown targets in cardiomyocytes. Within 2-3 mo, mice developed severe heart failure and cardiac fibrosis in the absence of hypertension or chronic hyperaldosteronism. Moreover, cardiac failure and fibrosis were fully reversible when MR antisense mRNA expression was subsequently suppressed.
Beggah
Ahmed T
AT
Institut National de la Santé et de la Recherche Médicale U478, Hôpital Bichat-Claude Bernard, AP-HP, Federative Institute of Research 02, 75870 Paris, France.
Escoubet
Brigitte
B
Puttini
Stefania
S
Cailmail
Stephane
S
Delage
Vanessa
V
Ouvrard-Pascaud
Antoine
A
Bocchi
Brigitte
B
Peuchmaur
Michel
M
Delcayre
Claude
C
Farman
Nicolette
N
Jaisser
Frederic
F
D000818:Animals; D001483:Base Sequence; D018076:DNA, Complementary; D004195:Disease Models, Animal; D005355:Fibrosis; D015870:Gene Expression; D006321:Heart; D006333:Heart Failure / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D008969:Molecular Sequence Data; D009206:Myocardium / Q000166:cytology / Q000473:pathology*; D016372:RNA, Antisense; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism*; D013148:Spironolactone / Q000494:pharmacology; D020257:Ventricular Remodeling
D018076:DNA, Complementary; D000451:Mineralocorticoid Receptor Antagonists; D016372:RNA, Antisense; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone