Transcriptomic Bioinformatic Analyses of Atria Uncover Involvement of Pathways Related to Strain and Post-translational Modification of Collagen in Increased Atrial Fibrillation Vulnerability in Intensely Exercised Mice.
Transcriptomic Bioinformatic Analyses of Atria Uncover Involvement of Pathways Related to Strain and Post-translational Modification of Collagen in Increased Atrial Fibrillation Vulnerability in Intensely Exercised Mice.
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心房的转录组生物信息学分析揭示了与胶原蛋白应变和翻译后修饰相关的通路在剧烈运动小鼠心房颤动脆弱性增加中的参与。
DOI：
10.3389/fphys.2020.605671
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发表时间：
2020
影响因子：
4
通讯作者：
Backx PH
中科院分区：
文献类型：
--
作者：
Oh Y;Yang S;Liu X;Jana S;Izaddoustdar F;Gao X;Debi R;Kim DK;Kim KH;Yang P;Kassiri Z;Lakin R;Backx PH
心房颤动（AF）是最常见的室上性心动过速，通常与心血管疾病（CVD）和心血管健康状况不佳有关。矛盾的是，耐力运动员也有发生房颤的风险。虽然已经确定持续性房颤与心房纤维化、肥厚和炎症有关，但剧烈运动的小鼠表现出类似的不良心房变化和房颤易感性增加，这需要肿瘤坏死因子（TNF）信号传导，即使心室结构和功能得到改善。为了确定运动引起的房室特异性和tnf依赖性心房变化背后的一些分子因素，我们对野生型和tnf敲除小鼠在运动2天、2周或6周后的心脏进行了转录组分析。与静脉压升高引起的心房拉伸在房颤促进中的中心作用一致，所有3个时间点都与心房中与机械传感（局灶黏着激酶、整合素和细胞-细胞通讯）、细胞外基质（ECM）和TNF通路相关的基因的差异调节有关，TNF似乎在基因变化中起纵容作用，而不是因果作用。重要的是，机械传感/ECM基因以及微管蛋白和肥大相关基因在运动2天后才被富集，而在2周和6周时被下调，这表明运动引起的早期反应性应变依赖性重构导致代偿性调整。此外，在较晚的时间点，胶原蛋白基因和参与胶原蛋白周转的基因也出现下调，这是一种反映衰老相关纤维化的模式。相比之下，心室与心房的基因差异调节少了两倍，独立于TNF。我们的研究结果表明，运动促进了ECM/机械传感通路中依赖tnf的心房转录组重塑，这与运动增加的预负荷和心房拉伸一致。我们认为类似的预负荷依赖机制是心血管疾病患者和运动员心房变化和房颤的原因。
Atrial Fibrillation (AF) is the most common supraventricular tachyarrhythmia that is typically associated with cardiovascular disease (CVD) and poor cardiovascular health. Paradoxically, endurance athletes are also at risk for AF. While it is well-established that persistent AF is associated with atrial fibrosis, hypertrophy and inflammation, intensely exercised mice showed similar adverse atrial changes and increased AF vulnerability, which required tumor necrosis factor (TNF) signaling, even though ventricular structure and function improved. To identify some of the molecular factors underlying the chamber-specific and TNF-dependent atrial changes induced by exercise, we performed transcriptome analyses of hearts from wild-type and TNF-knockout mice following exercise for 2 days, 2 or 6 weeks of exercise. Consistent with the central role of atrial stretch arising from elevated venous pressure in AF promotion, all 3 time points were associated with differential regulation of genes in atria linked to mechanosensing (focal adhesion kinase, integrins and cell-cell communications), extracellular matrix (ECM) and TNF pathways, with TNF appearing to play a permissive, rather than causal, role in gene changes. Importantly, mechanosensing/ECM genes were only enriched, along with tubulin- and hypertrophy-related genes after 2 days of exercise while being downregulated at 2 and 6 weeks, suggesting that early reactive strain-dependent remodeling with exercise yields to compensatory adjustments. Moreover, at the later time points, there was also downregulation of both collagen genes and genes involved in collagen turnover, a pattern mirroring aging-related fibrosis. By comparison, twofold fewer genes were differentially regulated in ventricles vs. atria, independently of TNF. Our findings reveal that exercise promotes TNF-dependent atrial transcriptome remodeling of ECM/mechanosensing pathways, consistent with increased preload and atrial stretch seen with exercise. We propose that similar preload-dependent mechanisms are responsible for atrial changes and AF in both CVD patients and athletes.
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影响因子：
37.8
作者：
Bradshaw AD;Baicu CF;Rentz TJ;Van Laer AO;Boggs J;Lacy JM;Zile MR
通讯作者：
Zile MR
影响因子：
4.8
作者：
D'Addario, M;Arora, PD;McCulloch, CAG
通讯作者：
McCulloch, CAG
影响因子：
4.8
作者：
D'Addario, M;Arora, PD;McCulloch, CAG
通讯作者：
McCulloch, CAG
DOI：
10.1152/ajpheart.00867.2011
发表时间：
2012-02-01
影响因子：
4.8
作者：
Cheng, Guangmao;Kasiganesan, Harinath;Cooper, George
通讯作者：
Cooper, George
影响因子：
5.7
作者：
Drca, Nikola;Wolk, Alicja;Larsson, Susanna C.
通讯作者：
Larsson, Susanna C.