Vascular endothelial growth factor promotes atrial arrhythmias by inducing acute intercalated disk remodeling.
Vascular endothelial growth factor promotes atrial arrhythmias by inducing acute intercalated disk remodeling.
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DOI：
10.1038/s41598-020-77562-5
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发表时间：
2020-11-24
影响因子：
4.6
通讯作者：
Veeraraghavan R
中科院分区：
文献类型：
--
作者：
Mezache L;Struckman HL;Greer-Short A;Baine S;Györke S;Radwański PB;Hund TJ;Veeraraghavan R
心房颤动（AF）是最常见的心律失常，与炎症有关。AF患者的炎症细胞因子水平升高，已知可促进血管渗漏，如血管内皮生长因子A（VEGF）。然而，血管渗漏和随后的心脏水肿对房性心律失常的发生的贡献仍然未知。先前的工作表明，心脏中的间质性水肿可以通过破坏富含心脏钠通道（NaV1.5）的心室肌细胞闰盘（ID）纳米结构域和减缓心脏传导来急性促进室性心律失常。有趣的是，在来自AF患者的心房样品中已经鉴定出ID纳米结构域的类似破坏。因此，我们测试了VEGF诱导的血管渗漏可以通过破坏ID纳米结构域和减缓心房传导来急性增加房性心律失常易感性的假设。用VEGF治疗小鼠心脏（30-60分钟，在临床相关水平）延长了心电图P波，增加了对快速起搏诱导的房性心律失常的易感性。光学电压标测显示VEGF治疗后心房传导减慢（基线时10 ± 0.4 cm/s vs. 21 ± 1 cm/s，p < 0.05）。透射电子显微镜检查显示，相对于对照组，VEGF处理的心脏中邻近间隙连接的ID位点处的膜间距增加（GJ; 64 ± 9 nm对对照组中的17 ± 1 nm，p < 0.05），以及邻近机械连接的位点处的膜间距增加（MJ; 63 ± 4 nm对对照组中的27 ± 2 nm，p < 0.05）。重要的是，超分辨率显微镜和定量图像分析显示，重组的NaV1.5远离密集的集群本地化附近的GJs和MJs的整个ID更弥漫的分布。总之，这些数据表明，VEGF可以急性易感，否则正常的心脏房性心律失常的动态破坏NaV1.5丰富的ID纳米结构域和心房传导减慢。这些数据强调炎症诱导的血管渗漏是AF发展和进展的潜在因素。
Atrial fibrillation (AF) is the most common arrhythmia and is associated with inflammation. AF patients have elevated levels of inflammatory cytokines known to promote vascular leak, such as vascular endothelial growth factor A (VEGF). However, the contribution of vascular leak and consequent cardiac edema to the genesis of atrial arrhythmias remains unknown. Previous work suggests that interstitial edema in the heart can acutely promote ventricular arrhythmias by disrupting ventricular myocyte intercalated disk (ID) nanodomains rich in cardiac sodium channels (NaV1.5) and slowing cardiac conduction. Interestingly, similar disruption of ID nanodomains has been identified in atrial samples from AF patients. Therefore, we tested the hypothesis that VEGF-induced vascular leak can acutely increase atrial arrhythmia susceptibility by disrupting ID nanodomains and slowing atrial conduction. Treatment of murine hearts with VEGF (30–60 min, at clinically relevant levels) prolonged the electrocardiographic P wave and increased susceptibility to burst pacing-induced atrial arrhythmias. Optical voltage mapping revealed slower atrial conduction following VEGF treatment (10 ± 0.4 cm/s vs. 21 ± 1 cm/s at baseline, p < 0.05). Transmission electron microscopy revealed increased intermembrane spacing at ID sites adjacent to gap junctions (GJs; 64 ± 9 nm versus 17 ± 1 nm in controls, p < 0.05), as well as sites next to mechanical junctions (MJs; 63 ± 4 nm versus 27 ± 2 nm in controls, p < 0.05) in VEGF–treated hearts relative to controls. Importantly, super-resolution microscopy and quantitative image analysis revealed reorganization of NaV1.5 away from dense clusters localized near GJs and MJs to a more diffuse distribution throughout the ID. Taken together, these data suggest that VEGF can acutely predispose otherwise normal hearts to atrial arrhythmias by dynamically disrupting NaV1.5-rich ID nanodomains and slowing atrial conduction. These data highlight inflammation-induced vascular leak as a potential factor in the development and progression of AF.
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影响因子：
16.6
作者：
Leo-Macias A;Agullo-Pascual E;Sanchez-Alonso JL;Keegan S;Lin X;Arcos T;Feng-Xia-Liang;Korchev YE;Gorelik J;Fenyö D;Rothenberg E;Rothenberg E;Delmar M
通讯作者：
Delmar M
影响因子：
4.6
作者：
Bonilla, Ingrid M.;Belevych, Andriy E.;Gyorke, Sandor
通讯作者：
Gyorke, Sandor
影响因子：
5.5
作者：
Greer-Short, Amara;Musa, Hassan;Hund, Thomas J.
通讯作者：
Hund, Thomas J.
炎症和氧化应激在心房颤动中的作用。
影响因子：
5.5
作者：
Li, Jie;Solus, Joseph;Chen, Qingxia;Rho, Young Hee;Milne, Ginger;Stein, C. Michael;Darbar, Dawood
通讯作者：
Darbar, Dawood
影响因子：
3.8
作者：
Fernandez-Cobo, M;Gingalewski, C;De Maio, A
通讯作者：
De Maio, A