Oxidative Stress and Inflammatory Modulation of Ca(2+) Handling in Metabolic HFpEF-Related Left Atrial Cardiomyopathy.
Oxidative Stress and Inflammatory Modulation of Ca(2+) Handling in Metabolic HFpEF-Related Left Atrial Cardiomyopathy.
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DOI：
10.3390/antiox9090860
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发表时间：
2020-09-14
期刊：
影响因子：
--
通讯作者：
Hohendanner F
中科院分区：
文献类型：
--
作者：
Bode D;Wen Y;Hegemann N;Primessnig U;Parwani A;Boldt LH;M Pieske B;R Heinzel F;Hohendanner F
代谢综合征介导的心力衰竭伴射血分数保留（HFpEF）常伴有左心房（LA）心肌病，显著影响发病率和死亡率。我们在大鼠代谢性HFpEF模型中评估了活性氧（ROS）和内在炎症（TNF-α, IL-10）与LA心肌细胞功能失调Ca2+稳态相关的作用。ZFS-1型肥胖大鼠在体内表现出HFpEF和心房心肌病的特征：左室（LV）质量、E/ E′和LA大小增加，左室射血分数保持不变。在体外，LA心肌细胞表现出更多的线粒体裂变（MitoTracker）和ros生成（H2DCF）。在野生型（WT）中，促炎TNF-α破坏细胞Ca2+稳态，而抗炎IL-10没有显著影响（共聚焦显微镜；Fluo-4）。在HFpEF中，TNF-α对与TNF-α受体表达降低相关的Ca2+稳态没有影响（western blot）。此外，IL-10显著改善Ca2+的释放和再摄取，而IL-10受体-1的表达不变。代谢综合征介导的LA心肌病的氧化应激增加，抗炎治疗积极影响功能失调的Ca2+稳态。我们的数据表明，与hfpef相关的LA功能障碍患者可能受益于IL-10靶向治疗，这需要在临床前试验中进一步探索。
Metabolic syndrome-mediated heart failure with preserved ejection fraction (HFpEF) is commonly accompanied by left atrial (LA) cardiomyopathy, significantly affecting morbidity and mortality. We evaluate the role of reactive oxygen species (ROS) and intrinsic inflammation (TNF-α, IL-10) related to dysfunctional Ca2+ homeostasis of LA cardiomyocytes in a rat model of metabolic HFpEF. ZFS-1 obese rats showed features of HFpEF and atrial cardiomyopathy in vivo: increased left ventricular (LV) mass, E/e’ and LA size and preserved LV ejection fraction. In vitro, LA cardiomyocytes exhibited more mitochondrial-fission (MitoTracker) and ROS-production (H2DCF). In wildtype (WT), pro-inflammatory TNF-α impaired cellular Ca2+ homeostasis, while anti-inflammatory IL-10 had no notable effect (confocal microscopy; Fluo-4). In HFpEF, TNF-α had no effect on Ca2+ homeostasis associated with decreased TNF-α receptor expression (western blot). In addition, IL-10 substantially improved Ca2+ release and reuptake, while IL-10 receptor-1 expression was unaltered. Oxidative stress in metabolic syndrome mediated LA cardiomyopathy was increased and anti-inflammatory treatment positively affected dysfunctional Ca2+ homeostasis. Our data indicates, that patients with HFpEF-related LA dysfunction might profit from IL-10 targeted therapy, which should be further explored in preclinical trials.
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