Reversible cardiac fibrosis and heart failure induced by conditional expression of an antisense mRNA of the mineralocorticoid receptor in cardiomyocytes

doi:10.1073/pnas.102673599

Reversible cardiac fibrosis and heart failure induced by conditional expression of an antisense mRNA of the mineralocorticoid receptor in cardiomyocytes

^*Institut National de la Santé et de la Recherche Médicale U478 and ^†U426, Hôpital Bichat–Claude Bernard, AP-HP, Federative Institute of Research 02, 75870 Paris, France; ^‡Institut National de la Santé et de la Recherche Médicale U127, Federative Institute of Research 06, 75010 Paris, France; and ^§Pathology Unit and EA 3102, R. Debre Hospital, 75019 Paris, France

Edited by Maurice B. Burg, National Institutes of Health, Bethesda, MD, and approved March 7, 2002 (received for review December 17, 2001)

Abstract

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.

Footnotes

↵ ¶ To whom reprint requests should be addressed. E-mail: jaisser{at}bichat.inserm.fr.
This paper was submitted directly (Track II) to the PNAS office.
Data deposition: The sequences reported in this paper have been deposited in the European Molecular Biology Laboratory Database (accession nos. AJ311855 and AJ311856).
Abbreviations:

DT,

double-transgenic;

LV and RV,

left and right ventricle;

EF,

ejection fraction;

MR,

mineralocorticoid receptor;

mMR,

mouse MR;

MR-AS,

antisense mRNA of the murine MR;

ET,

ejection time;

EDD,

end diastolic diameter;

Vcfc,

mean velocity of circumferential fiber shortening