Published Online
on September 13, 2004

A more recent version of this article appeared on September 28, 2004

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Submitted on April 7, 2004
Revised on July 23, 2004
Accepted on July 28, 2004

Cardiac Specific Increase in Aldosterone Production Induces Coronary Dysfunction in Aldosterone Synthase-Transgenic Mice

Anne Garnier PhD, Jennifer K. Bendall PhD, Sebastien Fuchs MD, PhD, Brigitte Escoubet MD, PhD, Francesca Rochais MS, Jacqueline Hoerter PhD, Johnny Nehme MS, Marie-Lory Ambroisine MS, Noeleen De Angelis PhD, Gilles Morineau PhD, Pauline d’Estienne MS, Rodolphe Fischmeister PhD, Christophe Heymes PhD, Florence Pinet PhD, and Claude Delcayre PhD^*

From INSERM U572, Université Paris 7 (A.G., J.K.B., J.N., M.-L.A., P.D., C.H., C.D.), INSERM U36, Collège de France (S.F.), INSERM U426, CEFI IFR02, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Bichat (B.E.), and Laboratoire d’hormonologie, Hopital St Louis (G.M.), Paris, France; INSERM U446, Faculté de Pharmacie, Châtenay-Malabry, France (F.R., J.H., R.F.); Instituto Mario Negri, Milano, Italy (N.D.A.); and INSERM U508, Institut Pasteur, Lille, France (F.P.).

^* To whom correspondence should be addressed. E-mail: claude.delcayre{at}larib.inserm.fr.

Background--Elevated circulating aldosterone level is associated with impaired cardiovascular function. Although the mechanisms are not fully understood, aldosterone antagonists decrease total and cardiovascular mortality in heart failure and myocardial infarction. Aldosterone induces cardiac fibrosis in experimental models, and it is synthesized locally in rat heart. These observations suggest pathological effects of aldosterone in heart that remain unclear.

Methods and Results--Transgenic mice (TG) that overexpress the terminal enzyme of aldosterone biosynthesis, aldosterone synthase (AS), in heart have been raised by gene targeting with the -myosin heavy chain promoter. AS mRNA increased 100-fold and aldosterone concentration 1.7-fold in hearts of male TG mice relative to wild-type. No structural or myocardial alterations were evidenced, because ventricle/body weight, AT₁ and AT₂ receptor binding, and collagen content were unchanged in TG. No alteration in cardiac function was evidenced by echocardiography, isolated perfused heart, or whole-cell patch clamp experiments. In contrast, coronary function was impaired, because basal coronary flow was decreased in isolated perfused heart (-55% of baseline values), and vasodilatation to acetylcholine, bradykinin, and sodium nitroprusside was decreased by 75%, 60%, and 75%, respectively, in TG mice compared with wild-type, showing that the defect was not related to NO production.

Conclusions--Increased cardiac aldosterone production in male mice induces a major coronary endothelium-independent dysfunction with no detectable alterations in cardiac structure and function. However, coronary dysfunction may be harmful for coronary adaptation to increased flow demand.

Key words: aldosterone • hormones • genes • heart diseases

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