Sawa Yohei, Matsushita Naoko, Sato Sachiko, Ishida Nanae, Saito Maki, Sanbe Atsushi, Morino Yoshihiro, Taira Eiichi, Obara Mami, Hirose Masamichi
Division of Molecular and Cellular Pharmacology, Department of Pathophysiology and Pharmacology, Iwate Medical University School of Pharmaceutical Science.
Division of Cardiology, Department of Internal Medicine, Iwate Medical University, School of Medicine.
Int Heart J. 2021;62(3):616-626. doi: 10.1536/ihj.20-703.
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 (SS = 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 (SS = 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.
心房颤动（AF）是高血压相对常见的并发症。慢性高血压会诱导心脏HDAC6催化活性。然而，HDAC6激活是否导致高血压诱发的AF仍不确定。我们研究了慢性心脏HDAC6激活是否会诱导心房重塑，从而导致AF的发生。构建了在心肌细胞中特异性过表达活性HDAC6蛋白的HDAC6组成型活性转基因（TG）（HDAC6活性TG）小鼠，以研究慢性HDAC6激活对HDAC6活性TG和非转基因（NTG）小鼠心房电重构和结构重塑以及AF诱发的影响。与NTG小鼠相比，对HDAC6活性TG小鼠进行左心房短阵猝发起搏（刺激间期 = 30毫秒）15 - 30秒可显著增加持续性AF的发生率。与NTG小鼠心房相比，对分离的HDAC6活性TG小鼠进行左心房稳态起搏（刺激间期 = 80毫秒）可降低心房传导速度。HDAC6活性TG小鼠和NTG小鼠的心房大小相似。相比之下，与NTG小鼠心房相比，HDAC6活性TG小鼠心房的间质纤维化增加。虽然HDAC6活性TG小鼠和NTG小鼠心房中CX40和CX43的蛋白表达水平相似，但CX40和CX43在HDAC6活性TG小鼠心房中呈异质性分布，而在NTG小鼠心房中则没有。与NTG小鼠心房相比，HDAC6活性TG小鼠心房中白细胞介素6的基因表达增加。慢性心脏HDAC6激活可诱导心房电重构和结构重塑以及持续性AF。高血压诱导的心脏HDAC6催化活性可能在AF的发生发展中起重要作用。
