PREREQUISITE FOR CARDIAC ALDOSTERONE ACTION - MINERALOCORTICOID RECEPTOR AND 11-BETA-HYDROXYSTEROID DEHYDROGENASE IN THE HUMAN HEART

Background It has been proposed that aldosterone exerts direct effects on heart function, most notably on the development of myocardial fibr osis during ventricular hypertrophy in rat. Initial events in aldoster one action entail its binding to mineralocorticoid receptor (MR). Beca use MR displays similar affinities for aldosterone and glucocorticoids , the in vivo aldosterone selectivity of MR requires the presence of a n enzyme, 11 beta-hydroxysteroid dehydrogenase (11-HSD), which metabol izes glucocorticoids into inactive derivatives. Although evidence exis ts for the presence of MR in rodent heart, no data are available for h umans; moreover, the existence of cardiac 11-HSD is controversial. Met hods and Results The heart samples used originated from tissue removed during cardiac surgery in nontransplant patients or from endocavitary biopsies done for the follow-up of heart transplantation. The express ion of MR was examined at the mRNA and protein level by in situ hybrid ization with cRNA probes specific for human MR mRNA and by immuno-dete ction with two specific anti-MR antibodies. 11-HSD catalytic activity was determined by measurement of the metabolic rate of tritiated corti costeroids by cardiac samples. In nontransplanted hearts, an in situ h ybridization signal equivalent to that found in the whole kidney was p resent on cardiomyocytes. Specific immunolabeling of cardiomyocytes wi th anti-MR antibodies demonstrated the presence of the MR protein. Car diac 11-HSD activity was detected (243+/-26 fmol . 30 min(-1) . mg pro tein(-1)) and was dependent on the cofactor NAD, not NADP, suggesting that it corresponds to the form of the enzyme specifically responsible for MR protection. In transplanted hearts that presented severe alter ations, MR immunodetection was weaker and irregular, with no specific hybridization signal. Conclusions Our results demonstrate that MR is c oexpressed with 11-HSD in human heart, which thus possesses the cellul ar machinery required for direct aldosterone action.