Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Journal of the American College of Cardiology, 2010-02, Vol.55 (8), p.758-770

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2010

Quelle

Open access e-journals list

Beschreibungen/Notizen

• 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.