LNK/SH2B3 loss of function increases susceptibility to murine and human atrial fibrillation.
LNK/SH2B3 loss of function increases susceptibility to murine and human atrial fibrillation.
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LNK/SH2B3 功能丧失会增加小鼠和人类房颤的易感性。
DOI：
10.1093/cvr/cvae036
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发表时间：
2024
影响因子：
10.8
通讯作者：
Pitzer,Ash
中科院分区：
文献类型：
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作者：
Murphy,MatthewB;Yang,Zhenjiang;Subati,Tuerdi;Farber-Eger,Eric;Kim,Kyungsoo;Blackwell,DanielJ;Fleming,MatthewR;Stark,JoshuaM;VanAmburg,JosephC;Woodall,KaylenK;VanBeusecum,JustinP;Agrawal,Vineet;Smart,CharlesD;Pitzer,Ash
淋巴细胞衔接蛋白（LNK）是细胞因子和生长因子信号转导的负调节因子。SH 2B 3中的rs3184504变异降低LNK功能，并与心血管、炎症和血液学疾病（包括中风）相关。在小鼠中，Lnk的缺失导致炎症和氧化应激。我们假设Lnk −/−小鼠易患心房颤动（AF），rs3184504与人类AF和AF相关卒中相关。在炎症过程中，反应性脂质二羰基氧化损伤的主要组成部分，我们进一步假设，这些介质是关键的驱动程序的AF基板inLnk−/−mice.Methods and resultsLnk−/−或野生型（WT）小鼠与车辆或2-羟基苄胺（2-HOBA），二羰基清除剂，3个月。与WT相比，Lnk−/−小鼠显示AF持续时间增加，2-HOBA可预防AF持续时间增加。在Lnk −/−心房，动作电位延长，瞬时外向K+电流减少，迟发Na+电流增加，峰值Na+电流减少，促心律失常作用被2-HOBA抑制。线粒体功能障碍，特别是复合物I，在Lnk −/−心房中是明显的，而清除脂质二羰基阻止了这种异常。在Lnk −/−血浆和心房组织中，肿瘤坏死因子-α（TNF-α）和白细胞介素-1 β（IL-1β）分别升高，这两种因子均在体外引起电重构和生物能重构。抑制可溶性TNF-α可防止电重构和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。在一个大型数据库的基因型患者，rs3184504与AF，以及AF相关stroke.ConclusionThese研究结果确定了一个新的作用，LNK在AF的病理生理学在实验小鼠和人类。此外，反应性脂质二羰基对Lnk −/−小鼠的炎性AF底物至关重要，并主要通过电重构介导促炎细胞因子的促炎作用。
AimsThe lymphocyte adaptor protein (LNK) is a negative regulator of cytokine and growth factor signalling. The rs3184504 variant inSH2B3reduces 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 thatLnk−/−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 inLnk−/−mice.Methods and resultsLnk−/−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 theLnk−/−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 inLnk−/−atria, while scavenging lipid dicarbonyls prevented this abnormality. Tumour necrosis factor-α (TNF-α) and interleukin-1 beta (IL-1β) were elevated inLnk−/−plasma and atrial tissue, respectively, both of which caused electrical and bioenergetic remodellingin 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.ConclusionThese 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 inLnk−/−mice and mediate the pro-arrhythmic effects of pro-inflammatory cytokines, primarily through electrical remodelling.