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Chronic HDAC6 Activation Induces Atrial Fibrillation Through Atrial Electrical and Structural Remodeling in
Yohei Sawa1,2, Naoko Matsushita2, Sachiko Sato3
1Division of Molecular and Cellular Pharmacology, Department of Pathophysiology and Pharmacology, Iwate Medical University School of Pharmaceutical Science.
Insights
Chronic cardiac HDAC6 activation promotes atrial remodeling and increases atrial fibrillation (AF) susceptibility in mice. This suggests HDAC6 plays a key role in hypertension-related AF development.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Pathophysiology
Background:
- Atrial fibrillation (AF) is a common complication of hypertension.
- Hypertension is known to induce cardiac Histone Deacetylase 6 (HDAC6) catalytic activity.
- The specific role of HDAC6 activation in hypertension-induced AF remains unclear.
Purpose of the Study:
- To investigate whether chronic cardiac HDAC6 activation leads to atrial remodeling and AF induction.
- To examine the effects of HDAC6 activation on atrial electrical and structural properties.
Main Methods:
- Created HDAC6 constitutively active transgenic (TG) mice overexpressing active HDAC6 in cardiomyocytes.
- Compared AF induction, atrial conduction velocity, atrial size, interstitial fibrosis, connexin expression, and interleukin 6 gene expression between HDAC6 active TG and non-transgenic (NTG) mice.
- Utilized left atrial burst pacing and steady-state atrial pacing protocols.
Main Results:
- HDAC6 active TG mice exhibited a significantly higher frequency of sustained AF compared to NTG mice.
- Atrial conduction velocity was decreased, and atrial interstitial fibrosis was increased in HDAC6 active TG mice.
- Heterogeneous distribution of CX40 and CX43, and increased interleukin 6 gene expression were observed in HDAC6 active TG atria.
Conclusions:
- Chronic cardiac HDAC6 activation induces atrial electrical and structural remodeling.
- HDAC6 activation contributes to sustained atrial fibrillation.
- HDAC6 catalytic activity in hypertension may be a critical factor in AF development.
Abstract:
Atrial fibrillation (AF) is a relatively common complication of hypertension. Chronic hypertension induces cardiac HDAC6 catalytic activity. However, whether HDAC6 activation contributes to hypertension-induced AF is still uncertain. We examined whether chronic cardiac HDAC6 activation-induced atrial remodeling, leading to AF induction.The HDAC6 constitutively active transgenic (TG) (HDAC6 active TG) mouse overexpressing the active HDAC6 protein, specifically in cardiomyocytes, was created to examine the effects of chronic HDAC6 activation on atrial electrical and structural remodeling and AF induction in HDAC6 active TG and non-transgenic (NTG) mice. Left atrial burst pacing (S1S1 = 30 msec) for 15-30 sec significantly increased the frequency of sustained AF in HDAC6 active-TG mice compared with NTG mice. Left steady-state atrial pacing (S1S1 = 80 msec) decreased the atrial conduction velocity in isolated HDAC6 active TG compared with NTG mouse atria. The atrial size was similar between HDAC6 active TG and NTG mice. In contrast, atrial interstitial fibrosis increased in HDAC6 active TG compared with that of NTG mouse atria. While protein expression levels of both CX40 and CX43 were similar between HDAC6 active TG and NTG mouse atria, a heterogeneous distribution of CX40 and CX43 occurred in HDAC6 active-TG mouse atria but not in NTG mouse atria. Gene expression of interleukin 6 increased in HDAC6 active TG compared with NTG mouse atria.Chronic cardiac HDAC6 activation induced atrial electrical and structural remodeling, and sustained AF. Hypertension-induced cardiac HDAC6 catalytic activity may play important roles in the development of AF.
