Increased expression of mineralocorticoid receptor in human atrial fibrillation and a cellular model of atrial fibrillation.
OBJECTIVE
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.
Tsai
Chia-Ti
CT
Division of Cardiology, Department of Internal Medicine, National Taiwan University, Taipei, Taiwan.
Chiang
Fu-Tien
FT
Tseng
Chuen-Den
CD
Hwang
Juey-Jen
JJ
Kuo
Kuan-Ting
KT
Wu
Cho-Kai
CK
Yu
Chih-Chieh
CC
Wang
Yi-Chih
YC
Lai
Ling-Ping
LP
Lin
Jiunn-Lee
JL
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000096:biosynthesis; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000450:Aldosterone / Q000096:biosynthesis*; D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis; D018161:Receptors, Mineralocorticoid / Q000096:biosynthesis*; D015398:Signal Transduction; D013252:Steroid 11-beta-Hydroxylase / Q000096:biosynthesis
D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D013252:Steroid 11-beta-Hydroxylase