Murphy Matthew B, Yang Zhenjiang, Subati Tuerdi, Farber-Eger Eric, Kim Kyungsoo, Blackwell Daniel J, Fleming Matthew R, Stark Joshua M, Van Amburg Joseph C, Woodall Kaylen K, Van Beusecum Justin P, Agrawal Vineet, Smart Charles D, Pitzer Ashley, Atkinson James B, Fogo Agnes B, Bastarache Julie A, Kirabo Annet, Wells Quinn S, Madhur Meena S, Barnett Joey V, Murray Katherine T
Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 559 PRB, Nashville, TN 37232, USA.
Department of Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA.
Cardiovasc Res. 2024 Jul 2;120(8):899-913. doi: 10.1093/cvr/cvae036.
The lymphocyte adaptor protein (LNK) is a negative regulator of cytokine and growth factor signalling. The rs3184504 variant in SH2B3 reduces LNK function and is linked to cardiovascular, inflammatory, and haematologic 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 the major components of oxidative injury, and we further hypothesized that these mediators are critical drivers of the AF substrate in Lnk-/- mice.
Lnk-/- or wild-type (WT) mice were treated with vehicle or 2-hydroxybenzylamine (2-HOBA), a dicarbonyl scavenger, for 3 months. Compared with 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, pro-arrhythmic 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. Tumour necrosis factor-α (TNF-α) and interleukin-1 beta (IL-1β) were elevated in Lnk-/- plasma and atrial tissue, respectively, both of which caused electrical and bioenergetic remodelling in vitro. Inhibition of soluble TNF-α prevented electrical remodelling 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.
These findings identify a novel role for LNK in the pathophysiology of AF in both experimental mice and humans. Moreover, reactive lipid dicarbonyls are critical to the inflammatory AF substrate in Lnk-/- mice and mediate the pro-arrhythmic effects of pro-inflammatory cytokines, primarily through electrical remodelling.
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基因中的rs3184504变异会降低LNK功能，并与心血管、炎症和血液系统疾病（包括中风）相关。在小鼠中，Lnk基因缺失会导致炎症和氧化应激。我们推测Lnk基因敲除（Lnk-/-）小鼠易患心房颤动（AF），且rs3184504与人类的AF及AF相关中风有关。在炎症过程中，反应性脂质二羰基化合物是氧化损伤的主要成分，我们进一步推测这些介质是Lnk-/-小鼠中AF基质的关键驱动因素。
给Lnk-/-或野生型（WT）小鼠注射载体或二羰基清除剂2-羟基苄胺（2-HOBA），持续3个月。与WT小鼠相比，Lnk-/-小鼠的AF持续时间增加，而2-HOBA可预防这种情况。在Lnk-/-心房中，动作电位延长，瞬时外向钾电流减少，晚期钠电流增加，峰值钠电流减少，这些促心律失常作用可被2-HOBA抑制。线粒体功能障碍，尤其是复合体I的功能障碍，在Lnk-/-心房中很明显，而清除脂质二羰基化合物可预防这种异常。肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）分别在Lnk-/-血浆和心房组织中升高，两者均可在体外引起电和生物能量重塑。抑制可溶性TNF-α可预防电重塑和AF易感性，而抑制IL-1β可改善线粒体呼吸，但对AF易感性无影响。在一个大型基因分型患者数据库中，rs3184504与AF以及AF相关中风有关。
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，反应性脂质二羰基化合物对Lnk-/-小鼠中的炎症性AF基质至关重要，并主要通过电重塑介导促炎细胞因子的促心律失常作用。
