INSERM UMR-S 769, LabEx LERMIT, DHU-Torino, Châtenay-Malabry, France.
J Am Coll Cardiol. 2012 Jun 12;59(24):2182-90. doi: 10.1016/j.jacc.2012.01.060.
This study was designed to examine whether a cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE), PDE4, is expressed in human atrium and contributes to the control of electrical stability.
Atrial fibrillation is accompanied by a profound remodeling of membrane receptors and alterations in cAMP-dependent regulation of Ca(2+) handling. Being responsible for cAMP hydrolysis, PDEs are likely to play a role in this setting. In the rodent heart, PDE4 contributes up to 60% of total cAMP-hydrolytic activity. However, its role in the human heart remains controversial.
L-type Ca(2+) current and spontaneous Ca(2+) release were recorded in isolated human atrial myocytes. Intracellular cAMP was measured by live cell imaging using a fluorescence resonance energy transfer-based sensor. Contractile force and arrhythmias were recorded in human atrial trabeculae. PDE activity was measured in human atrial tissue from patients in sinus rhythm and permanent atrial fibrillation.
PDE4 is expressed in human atrial myocytes and accounts for approximately 15% of total PDE activity. PDE4D represents the major PDE4 subtype. PDE4 inhibition increased intracellular cAMP and L-type Ca(2+) current and dramatically delayed their decay after a brief β-adrenergic stimulation. PDE4 inhibition also increased the frequency of spontaneous Ca(2+) release at baseline, as well as the contractile response and the incidence of arrhythmias in human atrial strips during β-adrenergic stimulation. Total PDE activity decreased with age, and the relative PDE4 activity was lower in patients with permanent atrial fibrillation than in age-matched sinus rhythm controls.
PDE4 is critical in controlling cAMP levels and thereby Ca(2+) influx and release in human atrial muscle, hence limiting the susceptibility to arrhythmias.
本研究旨在探讨环磷酸腺苷(cAMP)磷酸二酯酶(PDE)是否在人类心房中表达,并对电稳定性的控制起作用。
房颤时伴随着膜受体的深刻重构和 cAMP 依赖性调节 Ca(2+) 处理的改变。PDE 负责 cAMP 的水解,可能在这种情况下发挥作用。在啮齿动物心脏中,PDE4 贡献了高达 60%的总 cAMP 水解活性。然而,其在人类心脏中的作用仍存在争议。
在分离的人心房肌细胞中记录 L 型 Ca(2+) 电流和自发性 Ca(2+) 释放。通过使用基于荧光共振能量转移的传感器进行活细胞成像来测量细胞内 cAMP。在人类心房小梁中记录收缩力和心律失常。在窦性心律和永久性房颤患者的人类心房组织中测量 PDE 活性。
PDE4 在人类心房肌细胞中表达,占总 PDE 活性的约 15%。PDE4D 代表主要的 PDE4 亚型。PDE4 抑制增加了细胞内 cAMP 和 L 型 Ca(2+) 电流,并在短暂β-肾上腺素刺激后显著延迟其衰减。PDE4 抑制还增加了自发性 Ca(2+) 释放的基础频率,以及在β-肾上腺素刺激期间人类心房条带的收缩反应和心律失常的发生率。总 PDE 活性随年龄而降低,永久性房颤患者的相对 PDE4 活性低于年龄匹配的窦性心律对照组。
PDE4 对于控制人类心房肌肉中的 cAMP 水平至关重要,从而限制心律失常的易感性。Ca(2+) 内流和释放。