Altered Expression of Zonula occludens-1 Affects Cardiac Na(+) Channels and Increases Susceptibility to Ventricular Arrhythmias.
Altered Expression of Zonula occludens-1 Affects Cardiac Na(+) Channels and Increases Susceptibility to Ventricular Arrhythmias.
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Zonula occludens-1的表达改变会影响心脏NA（+）通道，并增加对心室心律不齐的敏感性。
DOI：
10.3390/cells11040665
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发表时间：
2022-02-14
期刊：
影响因子：
6
通讯作者：
Mohler PJ
中科院分区：
文献类型：
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作者：
El Refaey M;Coles S;Musa H;Stevens TL;Wallace MJ;Murphy NP;Antwi-Boasiako S;Young LJ;Manring HR;Curran J;Makara MA;Sas K;Han M;Koenig SN;Skaf M;Kline CF;Janssen PML;Accornero F;Borzok MA;Mohler PJ
Zonula occludens-1(ZO-1)是一种细胞内支架蛋白，它协调膜蛋白与上皮和包括心脏在内的特殊组织中的细胞骨架的锚定。有明确的证据支持细胞内辅助蛋白在心律失常发生中的中心作用，先前的研究发现ZO-1的表达改变与房室传导异常有关。在这里，我们利用人的心脏组织，我们鉴定了ZO-1的所有三个亚型，Canonical(转录变体1，TV1)，CRA_e(转录变体4，TV4)，以及在非衰竭心肌中额外表达的一个(转录变体3，TV3)。为了研究ZO-1在室性心律失常发生中的作用，我们建立了单倍体缺陷的ZO-1小鼠模型(ZO-1+/−)。ZO-1+/−小鼠表现出间隙连接蛋白43蛋白表达和定位异常。虽然ZO-1+/−小鼠在基线时没有表现出心功能异常，但肾上腺素能刺激导致节律异常，包括室性早搏和双配对。在基线时，ZO-1+/−小鼠的心肌细胞表现出动作电位持续时间延长和自发去极化，其中ZO-1+/−细胞表现出频繁的主动(非起搏)舒张期去极化，导致自发活动和多个早期后除极(EAD)。在机制上，ZO-1缺乏的心肌细胞表现出钠电流密度(INa)的降低和对异丙肾上腺素刺激的敏感性增加。此外，ZO-1缺陷的心肌细胞表现出ICA电流的重塑，可能是一种代偿性改变。综上所述，我们的数据表明，ZO-1缺乏导致心肌基质易发生触发的心律失常。
Zonula occludens-1 (ZO-1) is an intracellular scaffolding protein that orchestrates the anchoring of membrane proteins to the cytoskeleton in epithelial and specialized tissue including the heart. There is clear evidence to support the central role of intracellular auxiliary proteins in arrhythmogenesis and previous studies have found altered ZO-1 expression associated with atrioventricular conduction abnormalities. Here, using human cardiac tissues, we identified all three isoforms of ZO-1, canonical (Transcript Variant 1, TV1), CRA_e (Transcript Variant 4, TV4), and an additionally expressed (Transcript Variant 3, TV3) in non-failing myocardium. To investigate the role of ZO-1 on ventricular arrhythmogenesis, we generated a haploinsufficient ZO-1 mouse model (ZO-1+/−). ZO-1+/− mice exhibited dysregulated connexin-43 protein expression and localization at the intercalated disc. While ZO-1+/− mice did not display abnormal cardiac function at baseline, adrenergic challenge resulted in rhythm abnormalities, including premature ventricular contractions and bigeminy. At baseline, ventricular myocytes from the ZO-1+/− mice displayed prolonged action potential duration and spontaneous depolarizations, with ZO-1+/− cells displaying frequent unsolicited (non-paced) diastolic depolarizations leading to spontaneous activity with multiple early afterdepolarizations (EADs). Mechanistically, ZO-1 deficient myocytes displayed a reduction in sodium current density (INa) and an increased sensitivity to isoproterenol stimulation. Further, ZO-1 deficient myocytes displayed remodeling in ICa current, likely a compensatory change. Taken together, our data suggest that ZO-1 deficiency results in myocardial substrate susceptible to triggered arrhythmias.