Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 45, Issue 6, Pages 715-723Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.yjmcc.2008.08.015
Keywords
Atrial arrhythmias; Histone deacetylases; Fibrosis; Connexin40; Heart failure
Categories
Funding
- NHLBI NIH HHS [R01 HL071546-05A1, R01 HL071546, K08 HL074108, K08 HL074108-05] Funding Source: Medline
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Atrial fibrosis influences the development of atrial fibrillation (AF), particularly in the setting of structural heart disease where angiotensin-inhibition is partially effective for reducing atrial fibrosis and AF. Histone-deacetylase inhibition reduces cardiac hypertrophy and fibrosis, so we sought to determine if the HDAC inhibitor trichostatin A (TSA) could reduce atrial fibrosis and arrhythmias. Mice over-expressing homeodomain-only Protein (HopX(Tg)), which recruits HDAC activity to induce cardiac hypertrophy were investigated in 4 groups (aged 14-18 weeks): wild-type (WT), HopX(Tg), HopX(Tg) mice treated with TSA for 2 weeks (TSA-HopX) and wild-type mice treated with TSA for 2 weeks (TSA-WT). These groups were characterized using invasive electrophysiology, atrial fibrosis measurements, atrial connexin immunocytochemistry and Myocardial angiotensin II measurements. Invasive electrophysiologic stimulation, using the same attempts in each group, induced more atrial arrhythmias in HopX(Tg) mice (48 episodes in 13 of 15 HopX(Tg) mice versus 5 episodes in 2 of 15 TSA-HopX mice, P < 0.001; versus 9 episodes in 2 of 15 WT mice, P < 0.001: versus no episodes in any TSA-WT mice, P < 0.001). TSA reduced atrial arrhythmia duration in HopX(Tg) mice (1307 +/- 289 ms versus 148 +/- 110 ms, P < 0.01) and atrial fibrosis (8.1 +/- 1.5% versus 3.9 +/- 0.4%, P < 0.001). Atrial connexin40 was lower in HopX(Tg), compared to WT mice, and TSA normalized the expression and size distribution of connexin40 gap junctions. Myocardial angiotensin II levels were similar between WT and HopX(Tg) mice (76.3 +/- 26.0 versus 69.7 +/- 16.6 pg/mg protein, P=NS). Therefore, it appears HDAC-inhibition reverses atrial fibrosis, connexin40 remodeling and atrial arrhythmia vulnerability independent of angiotensin II in cardiac hypertrophy. (C) 2008 Elsevier Inc. All rights reserved.
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