Increased Expression of Mineralocorticoid Receptor in Human Atrial Fibrillation and a Cellular Model of Atrial Fibrillation

Chia Ti Tsai, Fu Tien Chiang, Chuen Den Tseng, Juey Jen Hwang, Kuan Ting Kuo, Cho Kai Wu, Chih Chieh Yu, Yi Chih Wang, Ling Ping Lai, Jiunn Lee Lin

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

Objectives: This study was designed to evaluate the status of steroidogenesis proteins and de novo synthesis of aldosterone in the atrium, and relationships of these factors to atrial fibrillation (AF). Background: The role of mineralocorticoid in the pathogenesis of AF is unknown. Methods: We studied atrial expression of steroidogenesis proteins and aldosterone level in patients with and without AF, and in HL-1 atrial myocytes. We also investigated the electrophysiologic effects and signal transduction of aldosterone on atrial myocytes. Results: We found basal expressions of mineralocorticoid receptors (MRs), glucocorticoid receptors, and 11-beta-hydroxysteroid dehydrogenase type 2 (11bHSD2) but not 11-beta-hydroxylase (CYP11B1) or aldosterone synthase (CYP11B2) in human atria and HL-1 myocytes. There was no significant difference of mean atrial aldosterone level between patients with AF and those with normal sinus rhythm. However, patients with AF had a significantly higher atrial MR expression compared with those with normal sinus rhythm (1.73 ± 0.24-fold, p < 0.001). Using mouse HL-1 atrial myocytes as a cellular AF model, we found that rapid depolarization increased MR expression (1.97 ± 0.72-fold, p = 0.008) through a calcium-dependent mechanism, thus augmenting the genomic effect of aldosterone signaling as evaluated by MR reporter. Aldosterone increased intracellular oxidative stress through a nongenomic pathway, which was attenuated by nicotinamide adenine dinucleotide phosphate oxidase inhibitor diphenyleneiodonium, but not by MR-blockade spironolactone. Aldosterone increased expression of the alpha-1G and -1H subunits of the T-type calcium channel and thus increased the T-type calcium current (-13.6 ± 2.9 pA/pF vs. -4.5 ± 1.6 pA/pF, p < 0.01) and the intracellular calcium load through a genomic pathway, which were attenuated by spironolactone, but not by diphenyleneiodonium. Conclusions: Expression of MR increased in AF, thus augmenting the genomic effects of aldosterone. Aldosterone induced atrial ionic remodeling and calcium overload through a genomic pathway, which was attenuated by spironolactone. These results suggest that aldosterone may play a role in AF electrical remodeling and provide insight into the treatment of AF with MR blockade.

Original languageEnglish
Pages (from-to)758-770
Number of pages13
JournalJournal of the American College of Cardiology
Volume55
Issue number8
DOIs
Publication statusPublished - Feb 23 2010
Externally publishedYes

Keywords

  • aldosterone
  • atrial fibrillation
  • ionic remodeling
  • mineralocorticoid receptor
  • spironolactone

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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