Aims The lymphocyte adaptor protein (LNK) is a negative regulator of cytokine and growth factor signaling. The rs3184504 variant in SH2B3 reduces LNK function and is linked to cardiovascular, inflammatory, and hematologic disorders including stroke. In mice, deletion of Lnk causes inflammation and oxidative stress. We hypothesized that Lnk-/- mice are susceptible to atrial fibrillation (AF) and that rs3184504 is associated with AF and AF-related stroke in humans. During inflammation, reactive lipid dicarbonyls are a major component of oxidative injury, and we further hypothesized that these mediators are critical drivers of the AF substrate in Lnk-/- mice. Methods and Results Lnk-/- or wild-type (WT) mice were treated with vehicle or 2-hydroxybenzylamine (2-HOBA), a dicarbonyl scavenger, for 3 months. Compared to WT, Lnk-/- mice displayed increased AF duration that was prevented by 2-HOBA. In the Lnk-/- atria, action potentials were prolonged with reduced transient outward K+ current, increased late Na+ current, and reduced peak Na+ current, proarrhythmic effects that were inhibited by 2-HOBA. Mitochondrial dysfunction, especially for complex I, was evident in Lnk-/- atria, while scavenging lipid dicarbonyls prevented this abnormality. Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were elevated in Lnk-/- plasma and atrial tissue, respectively, both of which caused electrical and bioenergetic remodeling in vitro. Inhibition of soluble TNF-α prevented electrical remodeling and AF susceptibility, while IL-1β inhibition improved mitochondrial respiration but had no effect on AF susceptibility. In a large database of genotyped patients, rs3184504 was associated with AF, as well as AF-related stroke. Conclusions These findings identify a novel role for LNK in the pathophysiology of AF in both experimental mice and in humans. Moreover, reactive lipid dicarbonyls are critical to the inflammatory AF substrate in Lnk-/- mice and mediate the proarrhythmic effects of pro-inflammatory cytokines, primarily through electrical remodeling.

中文翻译：

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LNK/SH2B3 功能丧失会增加小鼠和人类房颤的易感性

目的 淋巴细胞衔接蛋白 (LNK) 是细胞因子和生长因子信号传导的负调节因子。SH2B3 中的 rs3184504 变异会降低 LNK 功能，并与心血管、炎症和血液疾病（包括中风）相关。在小鼠中，Lnk 缺失会导致炎症和氧化应激。我们假设 Lnk-/- 小鼠易患心房颤动 (AF)，并且 rs3184504 与人类 AF 和 AF 相关中风相关。在炎症过程中，反应性脂质二羰基是氧化损伤的主要成分，我们进一步假设这些介质是 Lnk-/- 小鼠中 AF 底物的关键驱动因素。方法和结果 Lnk-/- 或野生型 (WT) 小鼠用载体或二羰基清除剂 2-羟基苄胺 (2-HOBA) 治疗 3 个月。与 WT 相比，Lnk-/- 小鼠表现出 AF 持续时间延长，但 2-HOBA 可以阻止这种情况。在 Lnk-/- 心房中，动作电位延长，瞬时外向 K+ 电流减少，晚期 Na+ 电流增加，峰值 Na+ 电流减少，促心律失常作用可被 2-HOBA 抑制。线粒体功能障碍，尤其是复合物 I，在 Lnk-/- 心房中很明显，而清除脂质二羰基可以防止这种异常。Lnk-/-血浆和心房组织中的肿瘤坏死因子-α (TNF-α) 和白细胞介素-1β (IL-1β) 分别升高，这两者均引起体外电和生物能重塑。抑制可溶性 TNF-α 可以防止电重构和房颤易感性，而抑制 IL-1β 可以改善线粒体呼吸，但对房颤易感性没有影响。在基因分型患者的大型数据库中，rs3184504 与 AF 以及 AF 相关的中风相关。结论 这些发现确定了 LNK 在实验小鼠和人类 AF 病理生理学中的新作用。此外，反应性脂质二羰基对于 Lnk-/- 小鼠中的炎症 AF 底物至关重要，并主要通过电重塑介导促炎细胞因子的致心律失常作用。